Next Article in Journal
Oncology Therapeutics Targeting the Metabolism of Amino Acids
Next Article in Special Issue
Altered Expression Ratio of Actin-Binding Gelsolin Isoforms Is a Novel Hallmark of Mitochondrial OXPHOS Dysfunction
Previous Article in Journal
Highlights on Genomics Applications for Lysosomal Storage Diseases
Previous Article in Special Issue
Regulation of the Actin Cytoskeleton in Podocytes
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cells
Volume 9
Issue 8
10.3390/cells9081903
cells-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Myosin XVI in the Nervous System

by
Elek Telek
1,
András Kengyel
1 and
Beáta Bugyi
1,2,*
1
Department of Biophysics, Medical School, University of Pécs, Szigeti str. 12, H-7624 Pécs, Hungary
2
Szentágothai Research Centre, Ifjúság str. 34, H-7624 Pécs, Hungary
*
Author to whom correspondence should be addressed.
Cells 2020, 9(8), 1903; https://doi.org/10.3390/cells9081903
Submission received: 16 June 2020 / Revised: 7 August 2020 / Accepted: 12 August 2020 / Published: 15 August 2020
(This article belongs to the Special Issue Actin-Myosin Cytoskeleton Regulation and Function)
Browse Figures
Versions Notes

Abstract

:
The myosin family is a large inventory of actin-associated motor proteins that participate in a diverse array of cellular functions. Several myosin classes are expressed in neural cells and play important roles in neural functioning. A recently discovered member of the myosin superfamily, the vertebrate-specific myosin XVI (Myo16) class is expressed predominantly in neural tissues and appears to be involved in the development and proper functioning of the nervous system. Accordingly, the alterations of MYO16 has been linked to neurological disorders. Although the role of Myo16 as a generic actin-associated motor is still enigmatic, the N-, and C-terminal extensions that flank the motor domain seem to confer unique structural features and versatile interactions to the protein. Recent biochemical and physiological examinations portray Myo16 as a signal transduction element that integrates cell signaling pathways to actin cytoskeleton reorganization. This review discusses the current knowledge of the structure-function relation of Myo16. In light of its prevalent localization, the emphasis is laid on the neural aspects.

1. Introduction

Myosins are actin-based mechanochemical machines that convert the chemical energy of ATP hydrolysis to mechanical work and molecular movement along actin filaments [1,2]. Myosins are abundant in different types of tissues and involved in a large variety of cellular functions. Amongst these, several classes of the myosin superfamily (class I, II, III, V, VI, VII, IX, X, XV and XVI) are expressed in the nervous system [3,4]. Unequivocally, myosins play essential roles in the development and functioning of neural cells; and are implicated in diverse processes, such as neuroblast differentiation, neuronal migration, growth cone motility, axonal growth and transport or synaptic functions [3,4]. Myosins (myosin I, II, V, III, VI, VII, IX and XV) are important in the functioning, maintenance and morphology of sensory cells, including the hair cells in the inner ear, as well as the photoreceptors in the retina [3,4,5]. Based on the multiple functions of myosins in the nervous system, one can infer that they are implicated in human neurological disorders (Table 1). For a comprehensive overview of the neural functions of myosins, we direct the Readers to excellent reviews [3,4].

Myosin XVI

Myosin XVI (Myo16) as an unconventional myosin was discovered in a search for molecular motors associated to the motile events of nerve cells [26]. Myo16 is limited in distribution to the vertebrate lineage [27,28], and evolutionary related to the myosin III class [29]. The conserved motor domain of Myo16 is flanked by a unique combination of an N-terminal pre-motor extension (ankyrin domain, Myo16Ank) and a C-terminal tail (Figure 1). MYO16 (cytogenetic location: 13q33.3) encodes two distinct protein isoforms generated by alternative splicing that differ in the length of their C-terminus; the shorter Myo16a and the longer, predominant Myo16b [26].
The expression and localization of Myo16 is prevalent in the central nervous system [26,30]. The expression of the principal Myo16b isoform in rats and mouse was detected from early embryonic stages throughout the lifespan of the animals. Its expression exhibits a developmental stage dependent pattern peaking in the first and second postnatal weeks [26]. The predominant expression of Myo16 in neural tissues suggests its importance in the proper functioning of the brain, mainly during development but also in adulthood. In line with this, the alterations of the human MYO16; either single nuclear polymorphisms (SNPs), deletions or epigenetic modifications are associated with neurodegenerative and neuropsychiatric disorders, including schizophrenia, autism spectrum disorder (ASD), bipolar disorder subtype II (BP-II) and major depressive disorder (MDD) (Table 1) [21,22,23,24,25]. In addition to the association of the MYO16 gene to neurological disorders, many binding partners of Myo16 identified so far are central to normal brain functioning [31]. This implies that Myo16 may contribute to the functioning of the nervous system through its interactions with partner molecules.
Based on the recent biochemical and physiological analyses, Myo16 is emerging as an important regulator of the proper functioning of neural cells, although the exact molecular mechanisms underlying its role in the nervous system remain to be elucidated. Here, we provide an overview of the current understanding of the structural features, molecular interactions and cellular roles of Myo16 in the nervous system focusing on its unique domains: the N-terminal Myo16Ank and the C-terminal Myo16Tail. A more general overview of Myo16 can be found in Myosins. A Superfamily of Molecular Motors [31].

2. Interactions and Functions of Myosin XVI in the Nervous System

2.1. The N-terminal Myo16Ank Interacts with PP1c and Regulates Its Phosphatase Activity

Most of the myosins start with the conserved motor domain at the N-terminus of the polypeptide chain, but several classes (III, IX, XII, XV, XVI, XVIII) possess a pre-motor extension [29]. There are no structural or functional homologies among these pre-motor domains indicating that each evolved for a specific function [32,33,34,35,36]. The N-terminal extension of Myo16 (Myo16Ank) includes a myosin phosphatase N-terminal element (MyPhoNE), a KVxF motif and ankyrin repeats composed of tandem ankyrin motifs (Figure 1). These regions are conserved from fish to humans [31].
Based on its composition, Myo16Ank resembles the protein phosphatase 1 catalytic subunit (PP1c) binding site of the myosin phosphatase target/regulatory subunit 1 (MYPT1) of myosin light chain phosphatase (MLCP) [35]. MYPT1 is known to interact with PP1c [37]. The MYPT1:PP1c interaction is mediated through the KVxF motif, while the flanking regions provide additional contacts and tune the activity of the phosphatase [38]. Indeed, the association of Myo16 to the catalytic subunits PP1cα and PP1cγ was detected experimentally in postnatal rat cerebellum extracts in vivo, as well as by using recombinant proteins in vitro in surface plasmon resonance (SPR) studies [26,35]. Upon binding MYPT1 increases the dephosphorylation activity of PP1c towards the myosin regulatory light chain (RLC) target [37]. In contrast, the association of Myo16Ank to PP1c results in an opposite functional outcome; the phosphatase activity of the catalytic subunit towards the myosin RLC is significantly decreased in the Myo16Ank:PP1c complex in vitro [35]. Considering the large variability of the holoenzymes (see below) the opposite effect is not surprising.
The physiological relevance of this interaction and activity of Myo16Ank awaits further investigations, also targets of the Myo16Ank:PP1c have not been identified yet. PP1 is one of the most abundant protein phosphatases in eukaryotes; its catalytic subunit PP1c can interact with a large set of regulatory subunits in a mutually exclusive manner [38]. This results in the diversification of the holoenzymes with different specificity and functionality. Alternatively, the combinatorial control of the activity and substrate specificity of PP1c can be considered, whereby PP1c activity is increased or decreased depending on the combination of the regulatory subunits [39]. As an example, MYPT1 increases the activity of PP1c towards myosin RLC, but on the contrary, it decreases the PP1c activity towards glycogen phosphorylase [39]. The phosphorylation state of the target subunit can also affect the interaction and the functionality of the holoenzyme; serine and threonine phosphorylation of MYPT1 increases and decreases the phosphatase activity of the MYPT1:PP1c complex, respectively [38].

2.2. The-C terminal Myo16Tail Controls the Remodeling of the Actin Cytoskeleton by Linking PI3K and WAVE1

The C-terminal tails are highly versatile extensions among myosin classes containing different functional domains leading to diversified intracellular functions, such as anchoring, autoregulation, dimerization, cargo binding, cellular localization or protein-protein interaction [33,40,41,42]. In Myo16a isoform only a relatively short tail domain can be found at the C terminus, while a 590 amino acid tail extension (Myo16Tail, amino acids for rat Myo16) is a distinctive feature of the Myo16b isoform (Figure 1). The upstream region of Myo16Tail consists of a WAVE1 interacting region (WIR) followed by a neuronal tyrosine-phosphorylated adaptor for phosphoinositide 3-kinase (NYAP) homology motif (NHM) with two phosphorylation sites (Tyr1416 and Tyr1441) [30]. The downstream sequence of Myo16Tail possesses a considerable amount of structure-breaker proline residues and disorder-promoting amino acids [26,30,31,43]. These regions may attribute particularly important functions for Myo16Tail in the nervous system.
Myo16 was recently identified as NYAP3 amongst the neuronal tyrosine-phosphorylated adaptor for phosphoinositide 3-kinase proteins (NYAP 1-3) found in a screen for Src non-receptor tyrosine kinase family substrates by using a human hippocampus cDNA library [30]. The defining feature of the NYAP phosphoproteins is the presence of the NYAP homology motif (NHM) containing conserved tyrosine residues (YxxM) and a proline-rich stretch. Sequence analysis reveals the characteristic NHM motif in the C-terminal tail region of Myo16. It is specific for the Myo16b splice variant, the shorter Myo16a lacks this motif (Figure 1). In contrast to Myo16, NYAP1 and 2 do not possess any other regions N-terminally to their NHM [30].
Myo16/NYAP3 was shown to be involved in signal transduction by linking the PI3K pathway to the remodeling of the actin cytoskeleton [30] (Figure 2). Myo16 is phosphorylated at the conserved tyrosine residues (Y1416xxM and Y1441xxM) in the NHM by the Src tyrosine kinase Fyn in the mouse brain [30]. Fyn is involved in transmitting signals from diverse transmembrane receptors and implicated in synaptic efficacy and plasticity (long-term potentiation), learning and memory [44]. Myo16 phosphorylation is stimulated by Contactin5, a glycosylphosphatidylinositol (GPI) anchored membrane protein. Contactins, a subfamily of the immunoglobulin superfamily of neural cell-adhesion molecules (Ig-CAMs) are important for neuritogenesis and synapse formation [45]. Contactins can activate Src tyrosine kinase Fyn indirectly via protein tyrosine phosphatase α (PTPα) suggesting a potential pathway of Fyn-induced Myo16 phosphorylation [46,47]. Tyrosine-phosphorylated Myo16 interacts with the p85 regulatory subunit of the phosphoinositide 3-kinase (PI3K). Of note, this mode of activation is reminiscent of the direct recruitment and activation of PI3K by receptor tyrosine kinases [48,49]. The formation of the Myo16:PI3K complex eventuates the activation of the p110 catalytic subunit of the kinase and that of its downstream effectors, Akt and Rac1 [30]. The Rho family GTPase Rac1 is a canonical activator of the WAVE regulatory complex (WRC) that activates the Arp2/3 complex, which, in turn, catalyzes the assembly of branched actin meshwork [50,51]. Interestingly, Myo16 also associates with the Sra1 and Nap1 components of the WAVE1 component of the regulatory complex through the WAVE1 interacting region (WIR) intercalated between the motor domain and the NHM [30]. In the ternary complex, Myo16 can link and potentiate PI3K-Rac1 to its downstream WRC, thereby it can contribute to the activation of the WRC-Arp2/3 complex and consequently to the regulation of the actin cytoskeleton. Indeed, transient transfection of HeLa cells with Myo16Tail resulted in the collapse of actin structures that required both the functional WIR and NHM [30].
The physiological importance of the control of actin dynamics by Myo16 is further supported by studies in MYO16−/− mice [52]. Fluorescence recovery after photobleaching (FRAP) analysis of postsynaptic dendritic spines of Purkinje cells demonstrated that MYO16 depletion leads to a faster F-actin turnover rate. A similar effect was observed upon inhibiting either the WRC or the Arp2/3 complex both in wild-type and MYO16−/− mice implying that Myo16 controls actin dynamics through this pathway. Altogether, both in vitro and in vivo data indicate that Myo16 by activating the WRC-Arp2/3 complex machinery functions to attenuate actin cytoskeleton dynamics. The data are consistent with a hypothesis in which Myo16 integrates signaling events to actin network reorganization, thereby it acts as an indirect regulator of the actin cytoskeleton in the dendritic spines of Purkinje cells. On the other hand, the phenotypic analysis of the cerebellar molecular layer of MYO16−/− mice revealed a significant decrease in the number of synaptic vesicles and the area of presynaptic terminals in parallel fibers of granule cells [52]. Comprehensively, Myo16 appears to be important for the regulation of actin dynamics at postsynaptic sites, as well as for the organization of presynaptic terminals; and therefore may be important in the normal structure, function and plasticity of granule cell-Purkinje cell synapses (Figure 3).
The physiological relevance of Myo16 in neural functioning was assayed in animal studies [30,52,53]. In the triple KO mice for all the three NYAP proteins including Myo16/NYAP3 a reduction in brain size and weight was observed that may be indicative of neurite hypotrophy [30]. In single knockout MYO16 mice neither apparent abnormalities in the cerebellar anatomy nor change in selected synaptic markers were detected [52]. Behavioral analyses of MYO16−/− mice revealed no phenotypes and dysfunctions in locomotor activity, motor learning and social interaction; behaviors altered in the mouse model of ASD. Although the epigenetic control of MYO16 was described upon experience-based learning (contextual fear conditioning) in mouse [53].
The NYAP1-3 proteins are encoded by different genes (chromosomal location: NYAP1 7q22.1, NAPY2 2q36.3, NYAP3 13q33.3) [54]. The three NYAP proteins share the NHM region characterized by the conserved tyrosine residues (YxxM) and a proline-rich stretch. They are all phosphorylated, and connect the PI3K activation to WAVE1 signaling and to the remodeling of the actin cytoskeleton [30]. Importantly, in contrast to NYAP1 and 2, Myo16/NYAP3 possesses a motor domain and ankyrin repeats N-terminally to the NHM. The combination of the NHM with other domains is expected to endow Myo16 with distinct functional characteristics. However, the specificity or redundancy of the activities of NYAPs has not been investigated with this respect. NYAP1 was isolated first in a screen performed with a GST-Lyn fusion protein [30]. The Src protein kinase Lyn is closely related to Fyn and can be activated directly by Contactin [46]. The Lyn-mediated pathway might have relevance in the regulation and diversification of the functioning of NYAPs.

3. Regulatory Mechanisms Controlling the Motor Function

In support of being a generic motor protein, Myo16b interacts with F-actin in an ATP-dependent fashion in rat brain (P8) extracts [26]. The F-actin association is further supported by the localization of GFP-Myo16 heavy chain to F-actin rich structures in the dendritic spines of Purkinje cells [52]. However, the kinetic features of the motor activity and the nature of the regulatory mechanism of the mechanochemical cycle of Myo16 has not been identified yet.
The mechanics of myosin motors can be tuned by many different mechanisms that provides myosin-specific regulation; including phosphorylation of the motor domain, interaction between myosin heavy and light chains, as well as ‘backfolding’ [55,56,57].
Phosphorylation of the heavy chain of the motor domain can control the enzymatic and mechanochemical activities of myosins. The consensus phosphorylation site designated as the TEDS site [56,57,58]. The head phosphorylation activates the ATPase activity of myosin I of lower eukaryotes in Acanthaomeba [59,60], Dictyostelium [61,62] and yeast [63]. By contrast, the ATPase activity of Acanthamoeba myosin II is down-regulated by phosphorylation of the motor domain at the motor-actin interface [64]. The motor domain of human myosin IIIA has a glutamic acid at the TEDS site (660Ex16DAMAK680). Although it is autophosphorylated by its kinase domain at two threonines in the loop 2 region (T908 and T919) [65,66,67]. The covalent modification considerably increases the ATPase activity, influences the steps of the ATPase cycle and negatively regulates the actin binding affinity of myosin IIIA. In mouse myosin VI, threonine in the TEDS site (406Tx16DALAK426) is phosphorylated, although it does not influence the ATPase activity of the motor domain [68]. Myo16 adheres to the TEDS rule (722Dx16DLLAK742) [26,31]. Although conserved serine and threonine phosphorylation sites can be predicted in the P-loop as the part of the ATP-binding pocket, preceding the DLLAK motif and in the C-terminus of the motor (Figure 4, Table 2) speculating that the motor domain of Myo16 is still object to regulation by phosphorylation, similarly to myosin IIIA.
Besides the predicted phosphoresidues a putative ubiquitination site is found at Lys1029. Ubiquitination triggers proteolysis and protein degradation through the ubiquitin-proteasome pathway in which they are recognized by the 26S proteasome and degraded [69]. In line with this, the 26S proteasome was implicated in the degradation of Myo16 [70].
The association between the IQ motif(s) of myosin heavy chain in the neck domain and the members of the calmodulin family; calmodulin or calmodulin-like (essential and regulatory) light chains can regulate both the structural properties and the mechanical adaptation of the myosin holoenzyme [55,73]. In this context, Myo16 has a single IQ motif in the neck region (Figure 1), however, the light chain of Myo16 has not been identified yet.
The ‘backfolding’ mechanism described in class IIa, V, VI, VII and X myosins provides an inhibitory regulation manifested through intramolecular interactions between the N-, and C-terminus of myosin adjoining the motor domain [74,75,76,77,78]. To investigate the potential intramolecular interactions and hierarchy of Myo16, the motor domain was modeled by using rabbit skeletal heavy meromyosin II (skHMM) or non-muscle myosin 2B [35]. Cosedimentation and SPR analysis showed that Myo16Ank binds skHMM with micromolar affinity and enhance the actin-activated Mg2+-ATPase of the motor domain [35]. Besides, experiments suggest that recombinant Myo16Ank and Myo16Tail can interact with a micromolar affinity (unpublished data) [43]. The above ranges of affinities are coincident with cellular functions, in which reversible interactions can occur having low affinity and high specificity [79]. In light of these molecular interactions, one can hypothesize that the motor domain of Myo16 may be upregulated directly by Myo16Ank, while the association of Myo16Tail and Myo16Ank may downregulate the motor activity indirectly, thereby providing control of the motor function in the cellular context.

4. The Importance of Polyproline Sequences and Phosphorylation Sites

Polyproline (PP) proteins comprise proline-rich motifs that tend to form polyproline helix II (PP II helix) [80]. PP II helices represent solvent-exposed and amphipathic binding interfaces that are frequently found in globular proteins [81,82]. Their occurrence is probably more common in intrinsically disordered proteins or protein regions (IDPs, IDRs) lacking a well-defined structural organization [80,83]. The proline-rich sequences by providing exposed and dynamic binding sites can serve for rapid recruitment and interchange of proteins, while tandem proline-rich motifs as part of adaptor systems can function in the assembly of protein interaction networks [80,84]. In support of this, several ligands prefer proline-containing regions, such as Src-homology 3 (SH3) and WW domain proteins, as well as Enabled (Ena)/vasodilator-stimulated phosphoprotein (VASP) homology 1 (Ena-EVH1), Homer-EVH1 and profilin [80]. On the other hand, phosphorylation sites are prevalent in proline-rich sequences and disordered protein regions [85,86,87].
From this aspect, Myo16b possesses a considerable amount of structure-breaker proline residues, phosphosites and disorder-promoting amino acids in the C-terminal Myo16Tail [26,30,31]. In line with this, Myo16b is phosphorylated by Src family kinase Fyn at two phosphotyrosines (Y1416xxM and Y1441xxM) found in the NHM region of Myo16Tail [30]. The binding site of Fyn in Myo16 has not been identified yet. Src family of protein kinases possess consecutive SH2 and SH3 domains that mediate both intra-, and intermolecular interactions [88]. The SH3 interaction module consists of a peptide-binding pocket that can recognize ligands with a PxxP consensus motif, and also divergent, non-consensus target sites [89,90]. Myo16Tail contains canonical PxxP recognition sequences, the SH3 domain of Fyn might interact with these regions to position Myo16 adjacent to the SH1 tyrosine kinase domain. Phosphorylation of Myo16b eventuates the recruitment and activation of PI3K [30]. The SH2 domain of the p85 regulatory subunit binds preferentially phosphotyrosines in the YPxxM phosphopeptide consensus sequence, indicating that the association of Myo16 and PI3K is likely to be mediated by this region [48]. In support of this, the interaction of Myo16-p85/PI3K was found to be dependent on the phosphorylation state of Myo16 [30].
Profilin is an actin-binding protein that also binds proline-rich ligands, such as formins, VASP and the WAVE family proteins [50,80,91,92]. The protein has four isoforms (PFN1-4), each is encoded by a distinct gene (PFN1-4). PFN1 is a ubiquitous isoform, while PFN2 shows predominant expression in the brain. Both PFN1 and 2 are important for actin-based neuronal processes; PFN1 regulates axonal growth and regeneration and PFN2 is associated with synaptic plasticity [93,94]. Since Myo16 is involved in the remodeling of the actin cytoskeleton and its C-terminus is rich in prolines, profilin appears to be an attractive candidate to associate with the Myo16-mediated processes. Profilin-binding proteins contain a recognition site of XP5 (X is G, L, I, S or A), either as a single copy or present in tandem repeats [92]. The very C-terminal region of Myo16Tail conforms to this consensus by possessing a P5 motif preceded by an alanine. Albeit, no direct interaction was found between recombinant Myo16Tail and PFN1 in steady-state anisotropy experiments [43]. This suggests the lack of or weak profilin binding, alternatively, the profilin isoform-specific nature of the interaction can be considered [95]. On the other hand, PFN1 is phosphorylated by RhoA-associated coiled-coil containing protein kinase 1 (ROCK1) at Ser137 in vivo that is conserved between the PFN1 and 2 isoforms [96]. ROCK phosphorylation as a regulatory switch influences the interactions of profilin with its ligands by increasing its affinity to polyproline sequences and actin [97]. Interestingly, the PP1cα catalytic subunit was identified to dephosphorylate PFN1 at Ser137 [98]. No direct association between PP1c and PFN1 was detected in vitro, suggesting that profilin is targeted by a PP1-interacting protein; however, regulatory subunits of PP1c for profilin modification have not been identified yet.

5. Concluding Remarks

The confined expression in neural tissues, the structural characteristics and interactions of the vertebrate-specific unconventional myosin XVI class suggest that it has an important role in neural development and functioning. As a support of this, the genetic examinations underscore the significance of Myo16 in the pathomechanism of neurological disorders, such as schizophrenia, autism spectrum disorder, bipolar disorder subtype II and major depressive disorder. The effects of the genetic alterations of MYO16 on the function of the protein, as well as the molecular networks linking Myo16 to diseases, remain to be elucidated. Myo16 has a peculiar domain architecture that endows the protein with unique structural characteristics. As inherent for classic motor proteins, the direct actin interactions and the enzymatic characteristics of the isolated motor domain of Myo16 are still obscure. The generic motor domain of Myo16 is flanked by the N-terminal Myo16Ank and the C-terminal Myo16Tail extensions that appear to provide a molecular scaffold for versatile interactions. Myo16Ank interacts with the PP1c subunit and regulates its phosphatase activity [26,35]. This suggests that Myo16 may participate in the targeted dephosphorylation of proteins, however, the targets or the physiological relevance of this activity are not known yet. On the other hand, emerging evidence emphasizes that the C-terminus of Myo16 functions in linking the PI3K-WRC signaling pathway to actin cytoskeleton reorganization [30].
Altogether these findings indicate that Myo16 comprises a mechanism in which it acts as a signal transduction element. From this aspect, Myo16 resembles class III and IX myosins [32]. Significant recent advances started to decipher the molecular interactions and cellular functioning of Myo16, albeit, the exact physiological role of Myo16, the underlying molecular interactions and activities, as well as their spatio-temporal sequence, remain to be elucidated.

Author Contributions

Conceptualization, B.B., E.T., A.K.; writing—review and editing, E.T., B.B., A.K.; proofreading and supervision, B.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by OTKA grant, K 112794 „Molecular Mechanisms Underlying the Function of Myosin 16b” from the Hungarian Scientific Research Fund. The work was supported by the ÚNKP-17-3-1 New National Excellence Program of the Ministry of Human Capacities and by the European Union, European Social Fund, EFOP 3.6.1-16-2016-00004, EFOP-3.6.2-16-2017-00006 and GINOP-2.3.2-15-2016-00049 grants. Supported by PTE ÁOK-KA 2019-39 grant (A.K.).

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

References

  1. Frénal, K.; Foth, B.J.; Soldati, D. Myosin Class XIV and Other Myosins in Protists. In Myosins, A Superfamily of Molecular Motors; Series: Proteins and Cell Regulation; Coluccio, L.M., Ed.; Springer Netherlands: Heidelberg, Germany, 2008; pp. 421–440. [Google Scholar]
  2. Coluccio, L.M.; Myosins, A. Superfamily of Molecular Motors, 2nd ed.; Series: Advances in Experimental Medicine and Biology; Springer International Publishing: Cham, Switzerland, 2020. [Google Scholar]
  3. Brown, M.E.; Bridgman, P.C. Myosin Function in Nervous and Sensory Systems. J. Neurobiol. 2004, 58, 118–130. [Google Scholar] [CrossRef] [PubMed]
  4. Suter, D.M. Functions of Myosin Motor Proteins in the Nervous System. In Neurobiology of Actin, Advances in Neurobiology 5; Gallo, G., Lanier, L., Eds.; Springer Science and Business Media: Berlin, Germany, 2010; pp. 45–72. [Google Scholar]
  5. Wu, X.; Jung, G.; Hammer, J.A., 3rd. Functions of unconventional myosins. Curr. Opin. Cell Biol. 2000, 12, 42–51. [Google Scholar] [CrossRef]
  6. Newell-Litwa, K.A.; Horwitz, R.; Lamers, M.L. Non-Muscle myosin II in disease: Mechanisms and therapeutic opportunities. Dis. Model. Mech. 2015, 8, 1495–1515. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Lalwani, A.K.; Goldstein, J.A.; Kelley, M.J.; Luxford, W.; Castelein, C.M.; Mhatre, A.N. Human Nonsyndromic Hereditary Deafness DFNA17 Is Due to a Mutation in Nonmuscle Myosin MYH9. Am. J. Hum. Genet. 2000, 67, 1121–1128. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  8. Tsai, J.W.; Bremner, K.H.; Vallee, R.B. Dual subcellular roles for LIS1 and dynein in radial neuronal migration in live brain tissue. Nat. Neurosci. 2007, 10, 970–979. [Google Scholar] [CrossRef] [PubMed]
  9. Walsh, T.; Walsh, V.; Vreugde, S.; Hertzano, R.; Shahin, H.; Haika, S.; Lee, M.K.; Kanaan, M.; King, M.-C.; Avraham, K.B. From flies’ eyes to our ears: Mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30. Proc. Nalt. Acad. Sci. USA 2002, 99, 7518–7523. [Google Scholar] [CrossRef] [Green Version]
  10. Chen, Y.; Tian, L.; Zhang, F.; Liu, C.; Lu, T.; Ruan, Y.; Wang, L.; Yan, H.; Yan, J.; Liu, Q.; et al. Myosin Vb gene is associated with schizophrenia in Chinese Han population. Psychiatry Res. 2013, 207, 13–18. [Google Scholar] [CrossRef]
  11. Dong, J.; Wyss, A.; Yang, J.; Price, T.R.; Nicolas, A.; Nalls, M.; Tranah, G.; Franceschini, N.; Xu, Z.; Schulte, C.; et al. Genome-Wide Association Analysis of the Sense of Smell in U.S. Older Adults: Identification of Novel Risk Loci in African-Americans and European-Americans. Mol. Neurobiol. 2017, 54, 8021–8032. [Google Scholar] [CrossRef]
  12. Pastural, E.; Barrat, F.J.; Dufourcq-Lagelouse, R.; Certain, S.; Sanal, O.; Jabado, N.; Seger, R.; Griscelli, C.; Fischer, A.; Saint Basile de, G. Griscelli disease maps to chromosome 15q21 and is associated with mutations in the myosin-Va gene. Nat. Genet. 1997, 16, 289–292. [Google Scholar] [CrossRef]
  13. Avraham, K.B.; Hasson, T.; Steel, K.P.; Kingsley, D.M.; Russell, L.B.; Mooseker, M.S.; Copeland, N.G.; Jenkins, N.A. The mouse Snell’s waltzer deafness gene encodes an unconventional myosin required for structural integrity of inner ear hair cells. Nat. Genet. 1995, 11, 369–374. [Google Scholar] [CrossRef]
  14. Liu, X.Z.; Walsh, J.; Tamagawa, Y.; Kitamura, K.; Nishizawa, M.; Steel, K.P.; Brown, S.D.M. Autosomal dominant non syndromic deafness caused by a mutation in the myosin 7A gene. Nat. Genet. 1997, 17, 268–269. [Google Scholar] [CrossRef] [PubMed]
  15. Weil, D.; Blanchard, S.; Kaplan, J.; Guilford, P.; Gibson, F.; Walsh, J.; Mbruru, P.; Valera, A.; Levilliers, J.; Weston, M.D.; et al. Defective myosin VIIA gene responsible for Usher syndrome type 1B. Nature 1995, 374, 60–61. [Google Scholar] [CrossRef] [PubMed]
  16. Weil, D.; Kussel, P.; Blanchard, S.; Levy, G.; Levi-Acobas, F.; Drira, M.; Ayadi, H.; Petit, C. The autosomal recessive isolated deafness, DFNB2, and the Usher 1B syndrome are allelic defects of the myosin-VIIA gene. Nat. Genet. 1997, 16, 191–193. [Google Scholar] [CrossRef] [PubMed]
  17. Liu, X.Z.; Walsh, J.; Mburu, P.; Kendrick-Jones, J.; Cope, M.J.T.V.; Steel, K.P.; Brown, S.D.M. Mutations in the myosin VIIA gene caue non syndromic recessive deafness. Nat. Genet. 1997, 16, 188–190. [Google Scholar] [CrossRef]
  18. Gibson, F.; Walsh, J.; Mburu, P.; Varela, A.; Brown, K.A.; Antonio, M.; Beisel, K.W.; Steel, K.P.; Brown, S.D.M. A type VII myosin encoded by the mouse deafness gene shaker-1. Lett. Nat. 1995, 374, 62–64. [Google Scholar] [CrossRef]
  19. Probst, F.J.; Fridell, R.A.; Raphael, Y.; Saunders, T.L.; Wang, A.; Liang, Y.; Morell, R.J.; Touchman, J.W.; Lyons, R.H.; Noben-Trauth, K.; et al. Correction of Deafness in shaker-2 Mice by an Unconventional Myosin in a BAC Transgene. Science 1998, 280, 1444–1447. [Google Scholar] [CrossRef]
  20. Wang, A.; Liang, Y.; Fridell, R.A.; Probst, F.J.; Wilcox, E.R.; Touchman, J.W.; Morton, C.C.; Morell, R.J.; Noben-trauth, K.; Camper, A.; et al. Association of Unconventional Myosin MYO15 Mutations with Human Nonsyndromic Deafness DFNB3. Sci. New Ser. 1998, 280, 1447–1451. [Google Scholar] [CrossRef] [Green Version]
  21. Gross, J.A.; Pacis, A.; Chen, G.G.; Drupals, M.; Lutz, P.E.; Barreiro, L.B.; Turecki, G. Gene-body 5-hydroxymethylation is associated with gene expression changes in the prefrontal cortex of depressed individuals. Transl. Psychiatry 2017, 7, e1119. [Google Scholar] [CrossRef] [Green Version]
  22. Liu, Y.F.; Sowell, S.M.; Luo, Y.; Chaubey, A.; Cameron, R.S.; Kim, H.G.; Srivastava, A.K. Autism and intellectual disability-associated KIRREL3 interacts with neuronal proteins MAP1B and MYO16 with potential roles in neurodevelopment. PLoS ONE 2015, 10, e0123106. [Google Scholar] [CrossRef]
  23. Rodriguez-Murillo, L.; Xu, B.; Roos, J.L.; Abecasis, G.R.; Gogos, J.A.; Karayiorgou, M. Fine mapping on chromosome 13q32-34 and brain expression analysis implicates MYO16 in schizophrenia. Neuropsychopharmacology 2014, 39, 934–943. [Google Scholar] [CrossRef] [Green Version]
  24. Kao, C.; Chen, H.; Chen, H.; Yang, J.; Huang, M.; Chiu, Y.; Lin, S.; Lee, Y.; Liu, C.; Chuang, L.; et al. Identification of Susceptible Loci and Enriched Pathways for Bipolar II Disorder Using Genome-Wide Association Studies. Int. J. Neuropsychopharmacol. 2016, 19, 1–11. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Chang, S.C.; Pauls, D.L.; Lange, C.; Sasanfar, R.; Santangelo, S.L. Sex-specific association of a common variant of the XG gene with autism spectrum disorders. Am. J. Med. Genet. Part. B Neuropsychiatr. Genet. 2013, 162, 742–750. [Google Scholar] [CrossRef] [PubMed]
  26. Patel, K.G.; Liu, C.; Cameron, P.L.; Cameron, R.S. Myr 8, a novel unconventional myosin expressed during brain development associates with the protein phosphatase catalytic subunits 1alpha and 1gamma1. J. Neurosci. 2001, 21, 7954–7968. [Google Scholar] [CrossRef] [Green Version]
  27. Thompson, R.F.; Langford, G.M. Myosin superfamily evolutionary history. Anat. Rec. 2002, 268, 276–289. [Google Scholar] [CrossRef] [PubMed]
  28. Odronitz, F.; Kollmar, M. Drawing the tree of eukaryotic life based on the analysis of 2,269 manually annotated myosins from 328 species. Genome Biol. 2007, 8, 1–23. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  29. Sebé-Pedrós, A.; Grau-Bové, X.; Richards, T.A.; Ruiz-Trillo, I. Evolution and classification of myosins, a paneukaryotic whole-genome approach. Genome Biol. Evol. 2014, 6, 290–305. [Google Scholar] [CrossRef] [Green Version]
  30. Yokoyama, K.; Tezuka, T.; Kotani, M.; Nakazawa, T.; Hoshina, N.; Shimoda, Y.; Kakuta, S.; Sudo, K.; Watanabe, K.; Iwakura, Y.; et al. NYAP: A phosphoprotein family that links PI3K to WAVE1 signalling in neurons. EMBO J. 2011, 30, 4739–4754. [Google Scholar] [CrossRef] [Green Version]
  31. Bugyi, B.; Kengyel, A. Myosin XVI. In Myosins, A Superfamily of Molecular Motors; Series: Advances in Experimental Medicine and Biology; Lynne, M.C., Ed.; Springer International Publishing: Cham, Switzerland, 2020; pp. 405–419. [Google Scholar]
  32. Bähler, M. Are class III and class IX myosins motorized signalling molecules? Biochim. Biophys. Acta-Mol. Cell Res. 2000, 1496, 52–59. [Google Scholar] [CrossRef] [Green Version]
  33. Sellers, J.R. Myosins: A diverse superfamily. Biochim Biophys Acta-Mol. Cell Res. 2000, 1496, 3–22. [Google Scholar] [CrossRef] [Green Version]
  34. Bird, J.E.; Takagi, Y.; Billington, N.; Strub, M.-P.; Sellers, J.R.; Friedman, T.B. Chaperone-enhanced purification of unconventional myosin 15, a molecular motor specialized for stereocilia protein trafficking. Proc. Nalt. Acad. Sci. USA 2014, 111, 1–6. [Google Scholar] [CrossRef] [Green Version]
  35. Kengyel, A.; Bécsi, B.; Kónya, Z.; Sellers, J.R.; Erdődi, F.; Nyitrai, M. Ankyrin domain of myosin 16 influences motor function and decreases protein phosphatase catalytic activity. Eur. Biophys. J. 2015, 44, 207–218. [Google Scholar] [CrossRef] [Green Version]
  36. Taft, M.; Latham, S. Myosin XVIII. In Myosins, A Superfamily of Molecular Motors; Series: Advances in Experimental Medicine and Biology; Lynne, M.C., Ed.; Springer International Publishing: Cham, Switzerland, 2020; pp. 421–438. [Google Scholar]
  37. Hartshorne, D.J.; Ito, M.; Erdödi, F. Myosin light chain phosphatase: Subunit composition, interactions and regulation. J. Muscle Res. Cell Motil. 1998, 19, 325–341. [Google Scholar] [CrossRef] [PubMed]
  38. Cohen, P.T.W. Protein phosphatase 1 – targeted in many directions. J. Cell Sci. 2020, 115, 241–256. [Google Scholar]
  39. Bollen, M. Combinatorial control of protein phosphatase-1. TRENDS Biochem. Sci. 2001, 26, 426–430. [Google Scholar] [CrossRef]
  40. Hartman, M.A.; Finan, D.; Sivaramakrishnan, S.; Spudich, J.A. Principles of Unconventional Myosin Function and Targeting. Annu. Rev. Cell Dev. Biol. 2016, 27, 133–155. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  41. Krendel, M.; Mooseker, M.S. Myosins: Tails (and Heads) of Functional Diversity. Physiology 2005, 20, 239–251. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Foth, B.J.; Goedecke, M.C.; Soldati, D. New insights into myosin evolution and classification. Proc. Nalt. Acad. Sci. USA 2006, 103, 3681–3686. [Google Scholar] [CrossRef] [Green Version]
  43. Kengyel, A.; Telek, E.; Kónya, Z.; Bécsi, B.; Erdődi, F.; Nyitrai, M. Interactions and Functions of Myosin 16 Domains. Biophys. J. 2017, 112, 267a. [Google Scholar] [CrossRef]
  44. Salter, M.W.; Kalia, L.V. SRC kinases: A hub for NMDA receptor regulation. Nat. Rev. Neurosci. 2004, 5, 317–328. [Google Scholar] [CrossRef]
  45. Mercati, O.; Danckaert, A.; André-Leroux, G.; Bellinzoni, M.; Gouder, L.; Watanabe, K.; Shimoda, Y.; Grailhe, R.; De Chaumont, F.; Bourgeron, T.; et al. Contactin 4, -5 and -6 differentially regulate neuritogenesis while they display identical PTPRG binding sites. Biol. Open 2013, 2, 324–334. [Google Scholar] [CrossRef] [Green Version]
  46. Tettamanti, G.; Kasahara, K.; Watanabe, K.; Kozutsumi, Y.; Oohira, A.; Yamamoto, T.; Sanai, Y. Association of GPI-Anchored Protein TAG-1 with Src-Family Kinase Lyn in Lipid Rafts of Cerebellar Granule Cells. Neurochem. Res. 2002, 27, 823–829. [Google Scholar]
  47. Zeng, L.; D’alessandri, L.; Kalousek, M.B.; Vaughan, L.; Pallen, C.J. Protein Tyrosine Phosphatase (PTP ) and Contactin Form a Novel Neuronal Receptor Complex Linked to the Intracellular Tyrosine Kinase fyn. J. Cell Biol. 1999, 147, 707–713. [Google Scholar] [CrossRef] [PubMed]
  48. Castellano, E.; Downward, J. Ras interaction with PI3K: More than just another effector pathway. Genes Cancer 2011, 2, 261–274. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  49. Vivanco, I.; Sawyers, C.L. The phosphatidylinositol 3-kinase-AKT pathway in humancancer. Nat. Rev. Cancer 2002, 2, 489–501. [Google Scholar] [CrossRef]
  50. Bugyi, B.; Carlier, M.-F. Control of Actin Filament Treadmilling in Cell Motility. Annu. Rev. Biophys. 2010, 39, 449–470. [Google Scholar] [CrossRef]
  51. Carver, R.J.; Chen, B.; Chou, H.-T.; Brautigam, C.A.; Xing, W.; Yang, S.; Henry, L.; Doolittle, L.K.; Walz, T.; Rosen, M.K. Rac1 GTPase activates the WAVE regulatory complex through two distinct binding sites. eLife 2017, 6, e29795. [Google Scholar]
  52. Roesler, M.K.; Lombino, F.L.; Freitag, S.; Schweizer, M.; Hermans-Borgmeyer, I.; Schwarz, J.R.; Kneussel, M.; Wagner, W. Myosin XVI Regulates Actin Cytoskeleton Dynamics in Dendritic Spines of Purkinje Cells and Affects Presynaptic Organization. Front. Cell Neurosci. 2019, 13, 330. [Google Scholar] [CrossRef] [Green Version]
  53. Koberstein, J.N.; Poplawski, S.G.; Wimmer, M.E.; Porcari, G.; Kao, C.; Gomes, B.; Risso, D.; Hakonarson, H.; Zhang, N.R.; Schultz, R.T.; et al. Learning-dependent chromatin remodeling highlights noncoding regulatory regions linked to autism. Sci. Signal. 2018, 11, eaan6500. [Google Scholar] [CrossRef] [Green Version]
  54. Amberger, J.S.; Bocchini, C.A.; Schiettecatte, F.; Scott, A.F.; Hamosh, A. OMIM.org: Online Mendelian Inheritance in Man (OMIM®), an Online catalog of human genes and genetic disorders. Nucleic Acids Res. 2015, 43, D789–D798. [Google Scholar] [CrossRef] [Green Version]
  55. Batters, C.; Veigel, C. Mechanics and Activation of Unconventional Myosins. Traffic 2016, 17, 860–871. [Google Scholar] [CrossRef] [Green Version]
  56. Heissler, S.M.; Sellers, J.R. Various Themes of Myosin Regulation. J. Mol. Biol. 2016, 428, 1927–1946. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Fili, N.; Toseland, C.P. Unconventional myosins: How regulation meets function. Int. J. Mol. Sci 2020, 21, 67. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Bement, W.M.; Mooseker, M.S. TEDS Rule: A Molecular Rationale for Differential Regulation of Myosins by Phosphorylation of the Heavy Chain Head. Cell Motil. Cytoskeleton 1995, 31, 87–92. [Google Scholar] [CrossRef] [PubMed]
  59. Brzeska, H.; Knaus, U.G.; Wang, Z.-Y.; Bokoch, G.M.; Korn, E.D. p21-activated kinase has substrate specificity similar to Acanthamoeba myosin I heavy chain kinase and activates Acanthamoeba myosin I. Proc. Nalt. Acad. Sci. USA 1997, 94, 1092–1095. [Google Scholar] [CrossRef] [Green Version]
  60. Brzeska, H.; Lynch, T.J.; Martin, B.; Korn, E.D. The Localization and Sequence of the Phosphorylation Sites of Acantharnoeba Myosins I. J. Biol. Chem. 1989, 264, 19340–19348. [Google Scholar]
  61. Dürrwang, U.; Fujita-Becker, S.; Erent, M.; Kull, F.J.; Tsiavaliaris, G.; Geeves, M.A.; Manstein, D.J. Dictyostelium myosin-IE is a fast molecular motor involved in phagocytosis. J. Cell Sci. 2006, 119, 550–558. [Google Scholar] [CrossRef] [Green Version]
  62. Fujita-Becker, S.; Dürrwang, U.; Erent, M.; Clark, R.J.; Geeves, M.A.; Manstein, D.J. Changes in Mg2+ ion concentration and heavy chain phosphorylation regulate the motor activity of a class I myosin. J. Biol. Chem. 2005, 280, 6064–6071. [Google Scholar] [CrossRef] [Green Version]
  63. Attanapola, S.L.; Alexander, C.J.; Mulvihill, D.P. Ste20-kinase-dependent TEDS-site phosphorylation modulates the dynamic localisation and endocytic function of the fission yeast class I myosin, Myo1. J. Cell Sci. 2009, 122, 3856–3861. [Google Scholar] [CrossRef] [Green Version]
  64. Liu, X.; Lee, D.Y.; Cai, S.; Yu, S.; Shu, S.; Levine, R.L.; Korn, E.D. Regulation of the actin-activated MgATPase activity of Acanthamoeba myosin II by phosphorylation of serine 639 in motor domain loop 2. Proc. Nalt. Acad. Sci. USA 2012, 110, E23–E32. [Google Scholar] [CrossRef] [Green Version]
  65. Komaba, S.; Inoue, A.; Maruta, S.; Hosoya, H.; Ikebe, M. Determination of human myosin III as a motor protein having a protein kinase activity. J. Biol. Chem. 2003, 278, 21352–21360. [Google Scholar] [CrossRef] [Green Version]
  66. Quintero, O.A.; Unrath, W.C.; Stevens, S.M.; Manor, U.; Kachar, B.; Yengo, C.M. Myosin 3A kinase activity is regulated by phosphorylation of the kinase domain activation loop. J. Biol. Chem. 2013, 288, 37126–37137. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Kambara, T.; Komaba, S.; Ikebe, M. Human myosin III is a motor having an extremely high affinity for actin. J. Biol. Chem. 2006, 281, 37291–37301. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Yoshimura, M.; Homma, K.; Saito, J.; Inoue, A.; Ikebe, R.; Ikebe, M. Dual Regulation of Mammalian Myosin VI Motor Function. J. Biol. Chem. 2001, 276, 39600–39607. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  69. Collins, G.A.; Goldberg, A.L. The Logic of the 26S Proteasome. Cell 2017, 169, 792–806. [Google Scholar] [CrossRef] [Green Version]
  70. Cameron, R.S.; Liu, C.; Pihkala, J.P.S. Myosin 16 levels fluctuate during the cell cycle and are downregulated in response to DNA replication stress. Cytoskeleton 2013, 70, 328–348. [Google Scholar] [CrossRef]
  71. Hornbeck, P.; Zhang, B.; Murray, B.; M Kornhauser, J.; Latham, V.; Skrzypek, E. PhosphoSitePlus, 2014: Mutations, PTMs and recalibrations. Nucleic. Acids Res. 2014, 43, 512–520. [Google Scholar] [CrossRef] [Green Version]
  72. Larkin, M.A.; Blackshields, G.; Brown, N.P.; Chenna, R.; Mcgettigan, P.A.; McWilliam, H.; Valentin, F.; Wallace, I.M.; Wilm, A.; Lopez, R.; et al. Clustal W and Clustal X version 2.0. Bioinformatics 2007, 23, 2947–2948. [Google Scholar] [CrossRef] [Green Version]
  73. Heissler, S.M.; Sellers, J.R. Myosin light chains: Teaching old dogs new tricks. Bioarchitecture 2014, 4, 169–188. [Google Scholar] [CrossRef] [Green Version]
  74. Milton, D.L.; Schneck, A.N.; Ziech, D.A.; Ba, M.; Facemyer, K.C.; Halayko, A.J.; Baker, J.E.; Gerthoffer, W.T.; Cremo, C.R. Direct evidence for functional smooth muscle myosin II in the 10S self-inhibited monomeric conformation in airway smooth muscle cells. Proc. Nalt. Acad. Sci. USA 2011, 108, 1421–1426. [Google Scholar] [CrossRef] [Green Version]
  75. Wang, F.; Thirumurugan, K.; Stafford, W.F.; Hammer, J.A.; Knight, P.J.; Sellers, J.R. Regulated Conformation of Myosin V. J. Biol. Chem. 2004, 279, 2333–2336. [Google Scholar] [CrossRef] [Green Version]
  76. Batters, C.; Brack, D.; Ellrich, H.; Averbeck, B.; Veigel, C. Calcium can mobilize and activate myosin-VI. Proc. Nalt. Acad. Sci. USA 2016, E1162–E1169. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Yang, Y.; Baboolal, T.G.; Siththanandan, V.; Chen, M.; Walker, M.L.; Knight, P.J.; Peckham, M.; Sellers, J.R. A FERM domain autoregulates Drosophila myosin 7a activity. Proc. Nalt. Acad. Sci. USA 2009, 106, 4189–4194. [Google Scholar] [CrossRef] [Green Version]
  78. Umeki, N.; Jung, H.S.; Sakai, T.; Sato, O.; Ikebe, R.; Ikebe, M. Phospholipid-dependent regulation of the motor activity of myosin X. Nat. Struct. Mol. Biol. 2011, 18, 783–788. [Google Scholar] [CrossRef] [PubMed]
  79. Wright, P.E.; Dyson, H.J. Intrinsically disordered proteins in cellular signaling and regulation. Nat. Rev. Mol. Cell Biol. 2015, 16, 18–29. [Google Scholar] [CrossRef] [PubMed]
  80. Kay, B.K.; Williamson, M.P.; Sudol, M. The importance of being proline: The interaction of proline-rich motifs in signaling proteins with their cognate domains. FASEB J. 2000, 14, 231–241. [Google Scholar] [CrossRef]
  81. Stapley, B.J.; Creamer, T.P. A survey of left-handed polyproline II helices. Protein Sci. 1999, 8, 587–595. [Google Scholar] [CrossRef] [Green Version]
  82. Alexei, A.A.; Michael, J.E.S. Left-handed polyproline II helices commonly occur in globular proteins. J. Mol. Biol. 1993, 229, 472–493. [Google Scholar]
  83. Adam, L.R.; Trevor, P.C. Polyproline II helical structure in protein unfolded states: Lysine peptides revisited. Protein Sci. 2002, 11, 980–985. [Google Scholar]
  84. Williamson, M.P. The structure and function of proline-rich regions in proteins. Biochem. J. 1994, 297, 249–260. [Google Scholar] [CrossRef] [Green Version]
  85. Steven, L.P.; Jasbinder, S.S. Mitogen-activated protein kinases: Versatile transducers for cell signaling. Trends Biochem. Sci. 1992, 17, 233–238. [Google Scholar]
  86. Florian, P.; James, A.B. Serine and Threonine Phosphorlyation. In Basic Neurochemistry, American Society for Neurochemistry; Elsevier Inc.: Amsterdam, The Netherlands, 2012; pp. 467–492. [Google Scholar]
  87. Iakoucheva, L.M.; Radivojac, P.; Brown, C.J.; O’Connor, T.R.; Sikes, J.G.; Obradovic, Z.; Dunker, A.K. The importance of intrinsic disorder for protein phosphorylation. Nucleic. Acids Res. 2004, 32, 1037–1049. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Yadav, S.S.; Miller, W.T. Cooperative activation of Src family kinases by SH3 and SH2 ligands. Cancer Lett. 2007, 257, 116–123. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. Gerbec, Z.J.; Thakar, M.S.; Malarkannan, S. The Fyn-ADAP axis: Cytotoxicity versus cytokine production in killer cells. Front. Immunol. 2015, 6, 472. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  90. Saksela, K.; Permi, P. SH3 domain ligand binding: What’s the consensus and where’s the specificity? FEBS Lett. 2012, 586, 2609–2614. [Google Scholar] [CrossRef] [Green Version]
  91. Vig, A.T.; Földi, I.; Szikora, S.; Migh, E.; Gombos, R.; Tóth, M.Á.; Huber, T.; Pintér, R.; Talián, G.C.; Mihály, J.; et al. The activities of the C-terminal regions of the formin protein Disheveled-associated activator of morphogenesis (DAAM) in actin dynamics. J. Biol. Chem. 2017, 292, 13566–13583. [Google Scholar] [CrossRef]
  92. Holt, M.R.; Koffer, A. Cell motility: Proline-rich proteins promote protrusions. Trends Cell Biol. 2001, 11, 38–46. [Google Scholar] [CrossRef]
  93. Michaelsen, K.; Murk, K.; Zagrebelsky, M.; Dreznjak, A.; Jockusch, B.M.; Rothkegel, M.; Korte, M. Fine-tuning of neuronal architecture requires two profilin isoforms. Proc. Nalt. Acad. Sci. USA 2010, 107, 15780–15785. [Google Scholar] [CrossRef] [Green Version]
  94. Pinto-Costa, R.; Sousa, S.C.; Leite, S.C.; Nogueira-Rodrigues, J.; Da Silva, T.F.; Machado, D.; Marques, J.; Costa, A.C.; Liz, M.A.; Bartolini, F.; et al. Profilin 1 delivery tunes cytoskeletal dynamics toward CNS axon regeneration. J. Clin. Investig. 2020, 130, 2024–2040. [Google Scholar] [CrossRef] [Green Version]
  95. Neidt, E.M.; Scott, B.J.; Kovar, D.R. Formin differentially utilizes profilin isoforms to rapidly assemble actin filaments. J. Biol. Chem. 2009, 284, 673–684. [Google Scholar] [CrossRef] [Green Version]
  96. Shao, J.; Welch, W.J.; Diprospero, N.A.; Diamond, M.I. Phosphorylation of profilin by ROCK1 regulates polyglutamine aggregation. Mol. Cell Biol. 2008, 28, 5196–5208. [Google Scholar] [CrossRef] [Green Version]
  97. Sathish, K.; Padma, B.; Munugalavadla, V.; Bhargavi, V.; Radhika, K.V.N.; Wasia, R.; Sairam, M.; Singh, S.S. Phosphorylation of profilin regulates its interaction with actin and poly (L-proline). Cell Signal. 2004, 16, 589–596. [Google Scholar] [CrossRef] [PubMed]
  98. Shao, J.; Diamond, M.I. Protein phosphatase 1 dephosphorylates profilin-1 at ser-137. PLoS ONE 2012, 7, e32802. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Cells 09 01903 g001 550
Figure 1. Domain structure of unconventional Myo16 isoforms. The number of amino acids corresponds to the rat Myo16 protein (accession number: Q9ERC1). Myo16a (1322 aa, 148.75 kDa) is composed of an N-terminal ankyrin domain (Myo16Ank) possessing a conserved myosin phosphatase N-terminal element (MyPhoNE), a KVxF sequence motif (protein phosphatase type 1 catalytic subunit (PP1c) binding motif) and eight ankyrin repeats (Ank). Myo16Ank is followed by the motor domain, a single IQ motif and a short C terminal region. The domain organization of the N-terminus of Myo16b (1912 aa, 210.56 kDa) is identical to that of Myo16a. Myo16b, following the IQ motif, has a longer C-terminal tail extension (Myo16Tail) including a WAVE1 interacting region (WIR), a neuronal tyrosine-phosphorylated adaptor for phosphoinositide 3-kinase (NYAP) homology motif (NHM) and proline-rich regions (PRR). The phosphotyrosines (Y1416 and Y1441) in the NHM motif are indicated (pY).
Figure 1. Domain structure of unconventional Myo16 isoforms. The number of amino acids corresponds to the rat Myo16 protein (accession number: Q9ERC1). Myo16a (1322 aa, 148.75 kDa) is composed of an N-terminal ankyrin domain (Myo16Ank) possessing a conserved myosin phosphatase N-terminal element (MyPhoNE), a KVxF sequence motif (protein phosphatase type 1 catalytic subunit (PP1c) binding motif) and eight ankyrin repeats (Ank). Myo16Ank is followed by the motor domain, a single IQ motif and a short C terminal region. The domain organization of the N-terminus of Myo16b (1912 aa, 210.56 kDa) is identical to that of Myo16a. Myo16b, following the IQ motif, has a longer C-terminal tail extension (Myo16Tail) including a WAVE1 interacting region (WIR), a neuronal tyrosine-phosphorylated adaptor for phosphoinositide 3-kinase (NYAP) homology motif (NHM) and proline-rich regions (PRR). The phosphotyrosines (Y1416 and Y1441) in the NHM motif are indicated (pY).
Cells 09 01903 g001
Cells 09 01903 g002 550
Figure 2. The C-terminal Myo16Tail in the reorganization of the actin cytoskeleton through the PI3K-WAVE1 pathway. Myo16Tail phosphorylation is triggered by Contactin5 through an unknown neuronal receptor (indicated with an X mark). Fyn binding to Myo16 is indirectly regulated by Contactin5 through a phosphatase (presumably via protein tyrosine phosphatase α (PTPα)). Tyrosine-phosphorylated Myo16 interacts directly with the p85 subunit of the phosphoinositide 3-kinase (PI3K) that is mediated by the NHM motif. The binding eventuates the activation of PI3K and its downstream effectors Akt and Rac1. Myo16 also interacts with the Sra1 and Nap1 subunits of WAVE1 through its WAVE1 interacting region. By simultaneous binding, Myo16 can bridge PI3K to WAVE1 and can contribute to the activation of WAVE1, thereby triggering the Arp2/3 complex-mediated remodeling of the actin cytoskeleton.
Figure 2. The C-terminal Myo16Tail in the reorganization of the actin cytoskeleton through the PI3K-WAVE1 pathway. Myo16Tail phosphorylation is triggered by Contactin5 through an unknown neuronal receptor (indicated with an X mark). Fyn binding to Myo16 is indirectly regulated by Contactin5 through a phosphatase (presumably via protein tyrosine phosphatase α (PTPα)). Tyrosine-phosphorylated Myo16 interacts directly with the p85 subunit of the phosphoinositide 3-kinase (PI3K) that is mediated by the NHM motif. The binding eventuates the activation of PI3K and its downstream effectors Akt and Rac1. Myo16 also interacts with the Sra1 and Nap1 subunits of WAVE1 through its WAVE1 interacting region. By simultaneous binding, Myo16 can bridge PI3K to WAVE1 and can contribute to the activation of WAVE1, thereby triggering the Arp2/3 complex-mediated remodeling of the actin cytoskeleton.
Cells 09 01903 g002
Cells 09 01903 g003 550
Figure 3. Schematic representation of the effects of Myo16 at parallel fiber-Purkinje cell synapses. Myo16 plays a role in the organization of the postsynaptic terminals of Purkinje cells by influencing the PI3K-WRC-Arp2/3 pathway that eventuates the downregulation of actin cytoskeleton dynamics. At the presynaptic site, Myo16 is implicated in the regulation of the number of synaptic vesicles, as well as of the morphological features of the parallel fiber terminal of granule cells. The X mark in the upper panel indicates the lack of interaction between Myo16, PI3K and WAVE1.
Figure 3. Schematic representation of the effects of Myo16 at parallel fiber-Purkinje cell synapses. Myo16 plays a role in the organization of the postsynaptic terminals of Purkinje cells by influencing the PI3K-WRC-Arp2/3 pathway that eventuates the downregulation of actin cytoskeleton dynamics. At the presynaptic site, Myo16 is implicated in the regulation of the number of synaptic vesicles, as well as of the morphological features of the parallel fiber terminal of granule cells. The X mark in the upper panel indicates the lack of interaction between Myo16, PI3K and WAVE1.
Cells 09 01903 g003
Cells 09 01903 g004 550
Figure 4. Post-translational prediction of Myo16 motor domain. Sequence analysis was performed using PhosphoSitePlus [71]. The total number of references shows the reliability of the prediction. Green squares indicate the phosphorylation sites while orange circle shows the ubiquitination site.
Figure 4. Post-translational prediction of Myo16 motor domain. Sequence analysis was performed using PhosphoSitePlus [71]. The total number of references shows the reliability of the prediction. Green squares indicate the phosphorylation sites while orange circle shows the ubiquitination site.
Cells 09 01903 g004
Table
Table 1. Association between different myosin classes and neurological disorders.
Table 1. Association between different myosin classes and neurological disorders.
Myosin 1
IIA
IIB		IIIAVA
VB		VIVIIAXVXVI
Myosin encoding geneNMMHC-IIA
NMMHC-IIB		MYO3AMYO5A
MYO5B		MYO6MYO7AMYO15MYO16
Alzheimer diseaseIIB
AutismIIB XVI
Schizophrenia VB XVI
Bipolar disorder subtype II XVI
Major depressive disorder XVI
Non-syndromic deafnessIIAIIIA VIIAXV
Snell’s waltzer syndrome VI
Usher syndrome VIIA
Griscelli disease VA
LissencephalyIIB
Sense of smell VB
Reference[6,7,8][9][10,11,12][13][14,15,16,17,18][19,20][21,22,23,24,25]
1 A and B indicates the isoform of the myosin.
Table
Table 2. Sequence alignment of Myo16 motor domain from different representatives of vertebrate classes in the aspect of post-translational modifications using Clustal-X [72].
Table 2. Sequence alignment of Myo16 motor domain from different representatives of vertebrate classes in the aspect of post-translational modifications using Clustal-X [72].
Motor Domain
Consensus
Amino Acid 1		P-LoopDLLAK Motif
(497–504 aa)(722–742 aa) S948S992K1029Y1075GY1077Y1090
* * : :..* **
HsS[GERGSGKS]DMIIRRHTIQIAEFFRDLLAKSSKYGYY
MmS[GERGSGKT]DVIIRRHTIQMAAFYRDLLAKSSKSGYY
RnS[GERGSGKT]DVIIRRHTTQIAAFYRDLLAKSSKYGYY
GgS[GESGSGKT]DMIVRRHTIEMAEFYRDLLAKSSKYGYY
XtS[GESGSGKT]DMITRRHSVDTAEFYRDLLAKSGKYGYY
DrS[GESGSGKS]DVITRRHTVEMSNHHRDLLTKCNKYGYY
Accession numbers of the sequences: Homo sapiens (Hs): Q9Y6X6, Mus musculus (Mm): Q5DU14, Rattus norvegicus (Rn): Q9ERC1, Gallus gallus (Gg): XP_416950.3, Xenopus tropicalis (Xt): A0A5G3IJG7, Danio rerio (Dr): F1QE80. Phosphorylation site prediction was analyzed in Figure 4. The conservation of the predicted phosphorylation/ubiquitination sites are labeled as fully conserved (*), strongly similar (:), weekly similar (.). Predicted phosphorylation sites and the ubiquitination site is colored by green and orange, respectively. 1Amino acid positions are given considering the sequence of the rat Myo16.

Share and Cite

MDPI and ACS Style

Telek, E.; Kengyel, A.; Bugyi, B. Myosin XVI in the Nervous System. Cells 2020, 9, 1903. https://doi.org/10.3390/cells9081903

AMA Style

Telek E, Kengyel A, Bugyi B. Myosin XVI in the Nervous System. Cells. 2020; 9(8):1903. https://doi.org/10.3390/cells9081903

Chicago/Turabian Style

Telek, Elek, András Kengyel, and Beáta Bugyi. 2020. "Myosin XVI in the Nervous System" Cells 9, no. 8: 1903. https://doi.org/10.3390/cells9081903

APA Style

Telek, E., Kengyel, A., & Bugyi, B. (2020). Myosin XVI in the Nervous System. Cells, 9(8), 1903. https://doi.org/10.3390/cells9081903

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop