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Biomolecules
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Molecular Functions of Microtubules
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Molecular Functions of Microtubules

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biophysics: Structure, Dynamics, and Function".

Deadline for manuscript submissions: closed (20 May 2023) | Viewed by 28654

Special Issue Editor

Dr. Scott Forth

E-Mail Website
Guest Editor
Department of Biological Sciences, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
Interests: microtubule; optics and photonics; optics and lasers; optical imaging; fluorescence imaging; cell mechanics; microscopy

Special Issue Information

Dear Colleagues,

The microtubule cytoskeleton provides cells with structural support, a means to perform mechanical work, cargo tracks for directional transport of vesicles and organelles, and a mechanism to segregate chromosomes during mitosis. To accomplish this wide array of tasks, microtubules are regulated by a host of motor and non-motor proteins, as well as directly modified via post-translational modifications. These factors alter microtubule polymerization dynamics, define new sites of nucleation, remodel filaments, and organize higher-order microtubule network architectures. Structural, biochemical, in vitro reconstitution, theoretical, and cell-based studies over the past few years have revealed many novel mechanisms by which microtubule function is regulated and have opened up new and exciting avenues of inquiry. Original manuscripts and reviews dealing with any and all aspects of molecular regulation of microtubules are solicited and welcome.

Dr. Scott Forth
Guest Editor

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Keywords

  • cytoskeleton
  • microtubule structure
  • microtubule-associated proteins
  • motor proteins
  • microtubule polymerization dynamics
  • microtubule post-translational modifications
  • microtubules in disease
  • microtubule networks
  • directional transport
  • modeling microtubules

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Published Papers (7 papers)

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Research

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17 pages, 9304 KiB  
Article
Quantifying Yeast Microtubules and Spindles Using the Toolkit for Automated Microtubule Tracking (TAMiT)
by Saad Ansari, Zachary R. Gergely, Patrick Flynn, Gabriella Li, Jeffrey K. Moore and Meredith D. Betterton
Biomolecules 2023, 13(6), 939; https://doi.org/10.3390/biom13060939 - 4 Jun 2023
Cited by 1 | Viewed by 1930
Abstract
Fluorescently labeled proteins absorb and emit light, appearing as Gaussian spots in fluorescence imaging. When fluorescent tags are added to cytoskeletal polymers such as microtubules, a line of fluorescence and even non-linear structures results. While much progress has been made in techniques for [...] Read more.
Fluorescently labeled proteins absorb and emit light, appearing as Gaussian spots in fluorescence imaging. When fluorescent tags are added to cytoskeletal polymers such as microtubules, a line of fluorescence and even non-linear structures results. While much progress has been made in techniques for imaging and microscopy, image analysis is less well-developed. Current analysis of fluorescent microtubules uses either manual tools, such as kymographs, or automated software. As a result, our ability to quantify microtubule dynamics and organization from light microscopy remains limited. Despite the development of automated microtubule analysis tools for in vitro studies, analysis of images from cells often depends heavily on manual analysis. One of the main reasons for this disparity is the low signal-to-noise ratio in cells, where background fluorescence is typically higher than in reconstituted systems. Here, we present the Toolkit for Automated Microtubule Tracking (TAMiT), which automatically detects, optimizes, and tracks fluorescent microtubules in living yeast cells with sub-pixel accuracy. Using basic information about microtubule organization, TAMiT detects linear and curved polymers using a geometrical scanning technique. Images are fit via an optimization problem for the microtubule image parameters that are solved using non-linear least squares in Matlab. We benchmark our software using simulated images and show that it reliably detects microtubules, even at low signal-to-noise ratios. Then, we use TAMiT to measure monopolar spindle microtubule bundle number, length, and lifetime in a large dataset that includes several S. pombe mutants that affect microtubule dynamics and bundling. The results from the automated analysis are consistent with previous work and suggest a direct role for CLASP/Cls1 in bundling spindle microtubules. We also illustrate automated tracking of single curved astral microtubules in S. cerevisiae, with measurement of dynamic instability parameters. The results obtained with our fully-automated software are similar to results using hand-tracked measurements. Therefore, TAMiT can facilitate automated analysis of spindle and microtubule dynamics in yeast cells. Full article
(This article belongs to the Special Issue Molecular Functions of Microtubules)
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22 pages, 9925 KiB  
Article
A Tale of 12 Tails: Katanin Severing Activity Affected by Carboxy-Terminal Tail Sequences
by K. Alice Lindsay, Nedine Abdelhamid, Shehani Kahawatte, Ruxandra I. Dima, Dan L. Sackett, Tara M. Finegan and Jennifer L. Ross
Biomolecules 2023, 13(4), 620; https://doi.org/10.3390/biom13040620 - 30 Mar 2023
Cited by 3 | Viewed by 2470
Abstract
In cells, microtubule location, length, and dynamics are regulated by a host of microtubule-associated proteins and enzymes that read where to bind and act based on the microtubule “tubulin code,” which is predominantly encoded in the tubulin carboxy-terminal tail (CTT). Katanin is a [...] Read more.
In cells, microtubule location, length, and dynamics are regulated by a host of microtubule-associated proteins and enzymes that read where to bind and act based on the microtubule “tubulin code,” which is predominantly encoded in the tubulin carboxy-terminal tail (CTT). Katanin is a highly conserved AAA ATPase enzyme that binds to the tubulin CTTs to remove dimers and sever microtubules. We have previously demonstrated that short CTT peptides are able to inhibit katanin severing. Here, we examine the effects of CTT sequences on this inhibition activity. Specifically, we examine CTT sequences found in nature, alpha1A (TUBA1A), detyrosinated alpha1A, Δ2 alpha1A, beta5 (TUBB/TUBB5), beta2a (TUBB2A), beta3 (TUBB3), and beta4b (TUBB4b). We find that these natural CTTs have distinct abilities to inhibit, most noticeably beta3 CTT cannot inhibit katanin. Two non-native CTT tail constructs are also unable to inhibit, despite having 94% sequence identity with alpha1 or beta5 sequences. Surprisingly, we demonstrate that poly-E and poly-D peptides are capable of inhibiting katanin significantly. An analysis of the hydrophobicity of the CTT constructs indicates that more hydrophobic polypeptides are less inhibitory than more polar polypeptides. These experiments not only demonstrate inhibition, but also likely interaction and targeting of katanin to these various CTTs when they are part of a polymerized microtubule filament. Full article
(This article belongs to the Special Issue Molecular Functions of Microtubules)
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20 pages, 44518 KiB  
Article
Mechanistic Analysis of CCP1 in Generating ΔC2 α-Tubulin in Mammalian Cells and Photoreceptor Neurons
by Takashi Hotta, Alexandra Plemmons, Margo Gebbie, Trevor A. Ziehm, Teresa Lynne Blasius, Craig Johnson, Kristen J. Verhey, Jillian N. Pearring and Ryoma Ohi
Biomolecules 2023, 13(2), 357; https://doi.org/10.3390/biom13020357 - 12 Feb 2023
Cited by 3 | Viewed by 2763
Abstract
An important post-translational modification (PTM) of α-tubulin is the removal of amino acids from its C-terminus. Removal of the C-terminal tyrosine residue yields detyrosinated α-tubulin, and subsequent removal of the penultimate glutamate residue produces ΔC2-α-tubulin. These PTMs alter the ability of the α-tubulin [...] Read more.
An important post-translational modification (PTM) of α-tubulin is the removal of amino acids from its C-terminus. Removal of the C-terminal tyrosine residue yields detyrosinated α-tubulin, and subsequent removal of the penultimate glutamate residue produces ΔC2-α-tubulin. These PTMs alter the ability of the α-tubulin C-terminal tail to interact with effector proteins and are thereby thought to change microtubule dynamics, stability, and organization. The peptidase(s) that produces ΔC2-α-tubulin in a physiological context remains unclear. Here, we take advantage of the observation that ΔC2-α-tubulin accumulates to high levels in cells lacking tubulin tyrosine ligase (TTL) to screen for cytosolic carboxypeptidases (CCPs) that generate ΔC2-α-tubulin. We identify CCP1 as the sole peptidase that produces ΔC2-α-tubulin in TTLΔ HeLa cells. Interestingly, we find that the levels of ΔC2-α-tubulin are only modestly reduced in photoreceptors of ccp1−/− mice, indicating that other peptidases act synergistically with CCP1 to produce ΔC2-α-tubulin in post-mitotic cells. Moreover, the production of ΔC2-α-tubulin appears to be under tight spatial control in the photoreceptor cilium: ΔC2-α-tubulin persists in the connecting cilium of ccp1−/− but is depleted in the distal portion of the photoreceptor. This work establishes the groundwork to pinpoint the function of ΔC2-α-tubulin in proliferating and post-mitotic mammalian cells. Full article
(This article belongs to the Special Issue Molecular Functions of Microtubules)
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Review

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19 pages, 2121 KiB  
Review
Highly Specialized Mechanisms for Mitochondrial Transport in Neurons: From Intracellular Mobility to Intercellular Transfer of Mitochondria
by Marta Zaninello and Camilla Bean
Biomolecules 2023, 13(6), 938; https://doi.org/10.3390/biom13060938 - 3 Jun 2023
Cited by 8 | Viewed by 6255
Abstract
The highly specialized structure and function of neurons depend on a sophisticated organization of the cytoskeleton, which supports a similarly sophisticated system to traffic organelles and cargo vesicles. Mitochondria sustain crucial functions by providing energy and buffering calcium where it is needed. Accordingly, [...] Read more.
The highly specialized structure and function of neurons depend on a sophisticated organization of the cytoskeleton, which supports a similarly sophisticated system to traffic organelles and cargo vesicles. Mitochondria sustain crucial functions by providing energy and buffering calcium where it is needed. Accordingly, the distribution of mitochondria is not even in neurons and is regulated by a dynamic balance between active transport and stable docking events. This system is finely tuned to respond to changes in environmental conditions and neuronal activity. In this review, we summarize the mechanisms by which mitochondria are selectively transported in different compartments, taking into account the structure of the cytoskeleton, the molecular motors and the metabolism of neurons. Remarkably, the motor proteins driving the mitochondrial transport in axons have been shown to also mediate their transfer between cells. This so-named intercellular transport of mitochondria is opening new exciting perspectives in the treatment of multiple diseases. Full article
(This article belongs to the Special Issue Molecular Functions of Microtubules)
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18 pages, 1251 KiB  
Review
Microtubule Regulation in Plants: From Morphological Development to Stress Adaptation
by An-Shan Hsiao and Ji-Ying Huang
Biomolecules 2023, 13(4), 627; https://doi.org/10.3390/biom13040627 - 30 Mar 2023
Cited by 10 | Viewed by 7746
Abstract
Microtubules (MTs) are essential elements of the eukaryotic cytoskeleton and are critical for various cell functions. During cell division, plant MTs form highly ordered structures, and cortical MTs guide the cell wall cellulose patterns and thus control cell size and shape. Both are [...] Read more.
Microtubules (MTs) are essential elements of the eukaryotic cytoskeleton and are critical for various cell functions. During cell division, plant MTs form highly ordered structures, and cortical MTs guide the cell wall cellulose patterns and thus control cell size and shape. Both are important for morphological development and for adjusting plant growth and plasticity under environmental challenges for stress adaptation. Various MT regulators control the dynamics and organization of MTs in diverse cellular processes and response to developmental and environmental cues. This article summarizes the recent progress in plant MT studies from morphological development to stress responses, discusses the latest techniques applied, and encourages more research into plant MT regulation. Full article
(This article belongs to the Special Issue Molecular Functions of Microtubules)
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35 pages, 4072 KiB  
Review
Computational Approaches to the Rational Design of Tubulin-Targeting Agents
by Helena Pérez-Peña, Anne-Catherine Abel, Maxim Shevelev, Andrea E. Prota, Stefano Pieraccini and Dragos Horvath
Biomolecules 2023, 13(2), 285; https://doi.org/10.3390/biom13020285 - 2 Feb 2023
Cited by 12 | Viewed by 4094
Abstract
Microtubules are highly dynamic polymers of α,β-tubulin dimers which play an essential role in numerous cellular processes such as cell proliferation and intracellular transport, making them an attractive target for cancer and neurodegeneration research. To date, a large number of known tubulin binders [...] Read more.
Microtubules are highly dynamic polymers of α,β-tubulin dimers which play an essential role in numerous cellular processes such as cell proliferation and intracellular transport, making them an attractive target for cancer and neurodegeneration research. To date, a large number of known tubulin binders were derived from natural products, while only one was developed by rational structure-based drug design. Several of these tubulin binders show promising in vitro profiles while presenting unacceptable off-target effects when tested in patients. Therefore, there is a continuing demand for the discovery of safer and more efficient tubulin-targeting agents. Since tubulin structural data is readily available, the employment of computer-aided design techniques can be a key element to focus on the relevant chemical space and guide the design process. Due to the high diversity and quantity of structural data available, we compiled here a guide to the accessible tubulin-ligand structures. Furthermore, we review different ligand and structure-based methods recently used for the successful selection and design of new tubulin-targeting agents. Full article
(This article belongs to the Special Issue Molecular Functions of Microtubules)
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Other

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8 pages, 3563 KiB  
Commentary
Structural Changes, Biological Consequences, and Repurposing of Colchicine Site Ligands
by Felipe Montecinos and Dan L. Sackett
Biomolecules 2023, 13(5), 834; https://doi.org/10.3390/biom13050834 - 14 May 2023
Cited by 5 | Viewed by 2398
Abstract
Microtubule-targeting agents (MTAs) bind to one of several distinct sites in the tubulin dimer, the subunit of microtubules. The binding affinities of MTAs may vary by several orders of magnitude, even for MTAs that specifically bind to a particular site. The first drug [...] Read more.
Microtubule-targeting agents (MTAs) bind to one of several distinct sites in the tubulin dimer, the subunit of microtubules. The binding affinities of MTAs may vary by several orders of magnitude, even for MTAs that specifically bind to a particular site. The first drug binding site discovered in tubulin was the colchicine binding site (CBS), which has been known since the discovery of the tubulin protein. Although highly conserved throughout eukaryotic evolution, tubulins show diversity in their sequences between tubulin orthologs (inter-species sequence differences) and paralogs (intraspecies differences, such as tubulin isotypes). The CBS is promiscuous and binds to a broad range of structurally distinct molecules that can vary in size, shape, and affinity. This site remains a popular target for the development of new drugs to treat human diseases (including cancer) and parasitic infections in plants and animals. Despite the rich knowledge about the diversity of tubulin sequences and the structurally distinct molecules that bind to the CBS, a pattern has yet to be found to predict the affinity of new molecules that bind to the CBS. In this commentary, we briefly discuss the literature evidencing the coexistence of the varying binding affinities for drugs that bind to the CBS of tubulins from different species and within species. We also comment on the structural data that aim to explain the experimental differences observed in colchicine binding to the CBS of β-tubulin class VI (TUBB1) compared to other isotypes. Full article
(This article belongs to the Special Issue Molecular Functions of Microtubules)
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