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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (15 July 2021) | Viewed by 32056

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Special Issue Editors

Dr. Giovanni Gotte

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Guest Editor

Dipartimento Neurosci Biomed & Movimento, Università degli Studi di Verona, I-37134 Verona, Italy
Interests: investigations of protein structure and function and oligomerization; pancreatic-type Ribonucleases (RNase A, BS-RNase, Onconase) covalent or non-covalent oligomerization through 3D domain swapping; antitumor activity of covalent or domain-swapped RNase oligomers, in vitro and in mice; studies of the mechanism(s) of RNases oligomerization; investigations on the in vitro alpha-synuclein aggregation
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Prof. Marta Menegazzi

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Co-Guest Editor

Department of Neuroscience, Biomedicine and Movement Sciences, Biochemistry Section, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy
Interests: natural products; inflammation; signal transduction; transcription factors; gene expression; antitumor therapy
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Special Issue Information

Dear Colleagues,

Protein oligomerization can occur either naturally or artificially, and can positively or negatively affect the properties of the native monomeric precursor.

The resulting oligomers can be small benign products, or larger amyloidogenic derivatives driving toward cross-beta fibrils that characterize neurodegenerative diseases.

The resulting species can be homo- or hetero-oligomers produced through artificial, or sometimes natural, intermolecular covalent cross-linking. Alternatively, they can be formed non-covalently (also naturally or artificially) through hydrophobic and/or electrostatic interactions, or following the so-called three-dimensional domain swapping (3D-DS) mechanism. These associations can occur as a consequence of modified environmental conditions, and the corresponding adducts can be stable or, sometimes, metastable.

Importantly, protein oligomerization can modify or light up the biological features of the native protein, or even switch-on properties lacked by the native monomer. This is particularly true for protein enzymes, whose self- or hetero-association can tune, properly or unwantedly, their activity.

This Special Issue welcomes the submission of original research papers and of reviews focused on data concerning one or more of the topics mentioned. The analysis and discussion of aspects connected with the possibility of better comprehending important features of human diseases and counteracting them are encouraged.

Prof. Giovanni Gotte
Prof. Dr. Marta Menegazzi
Guest Editors

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Keywords

protein structure and function
natural/artificial, covalent/non-covalent protein oligomers
end-to-end stacking, hydrophobic/electrostatic protein oligomerization
three-dimensional domain swapping (3D-DS) mechanism
enzymatic activity of protein oligomers
biological benign/harmful properties of protein oligomers
signal transduction of protein oligomers
cytotoxic/antitumor activity of protein oligomers
neurodegenerative effects of protein oligomers
protein fibrillogenesis

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Published Papers (9 papers)

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Editorial

Jump to: Research, Review

4 pages, 193 KiB

Open AccessEditorial

Protein Oligomerization

by Giovanni Gotte and Marta Menegazzi

Int. J. Mol. Sci. 2023, 24(13), 10648; https://doi.org/10.3390/ijms241310648 - 26 Jun 2023

Cited by 3 | Viewed by 1996

Abstract

Protein self-association is a biologically remarkable event that involves and affects the structural and functional properties of proteins [...] Full article

(This article belongs to the Special Issue Protein Oligomerization)

Research

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20 pages, 14945 KiB

Open AccessArticle

Slow Evolution toward “Super-Aggregation” of the Oligomers Formed through the Swapping of RNase A N-Termini: A Wish for Amyloidosis?

by Giovanni Gotte, Elena Butturini, Ilaria Bettin, Irene Noro, Alexander Mahmoud Helmy, Andrea Fagagnini, Barbara Cisterna and Manuela Malatesta

Int. J. Mol. Sci. 2022, 23(19), 11192; https://doi.org/10.3390/ijms231911192 - 23 Sep 2022

Cited by 3 | Viewed by 1601

Abstract

Natively monomeric RNase A can oligomerize upon lyophilization from 40% acetic acid solutions or when it is heated at high concentrations in various solvents. In this way, it produces many dimeric or oligomeric conformers through the three-dimensional domain swapping (3D-DS) mechanism involving both RNase A N- or/and C-termini. Here, we found many of these oligomers evolving toward not negligible amounts of large derivatives after being stored for up to 15 months at 4 °C in phosphate buffer. We call these species super-aggregates (SAs). Notably, SAs do not originate from native RNase A monomer or from oligomers characterized by the exclusive presence of the C-terminus swapping of the enzyme subunits as well. Instead, the swapping of at least two subunits’ N-termini is mandatory to produce them. Through immunoblotting, SAs are confirmed to derive from RNase A even if they retain only low ribonucleolytic activity. Then, their interaction registered with Thioflavin-T (ThT), in addition to TEM analyses, indicate SAs are large and circular but not “amyloid-like” derivatives. This confirms that RNase A acts as an “auto-chaperone”, although it displays many amyloid-prone short segments, including the 16–22 loop included in its N-terminus. Therefore, we hypothesize the opening of RNase A N-terminus, and hence its oligomerization through 3D-DS, may represent a preliminary step favoring massive RNase A aggregation. Interestingly, this process is slow and requires low temperatures to limit the concomitant oligomers’ dissociation to the native monomer. These data and the hypothesis proposed are discussed in the light of protein aggregation in general, and of possible future applications to contrast amyloidosis. Full article

(This article belongs to the Special Issue Protein Oligomerization)

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18 pages, 27032 KiB

Open AccessArticle

Dimerization of Human Angiogenin and of Variants Involved in Neurodegenerative Diseases

by Sabrina Fasoli, Ilaria Bettin, Riccardo Montioli, Andrea Fagagnini, Daniele Peterle, Douglas V. Laurents and Giovanni Gotte

Int. J. Mol. Sci. 2021, 22(18), 10068; https://doi.org/10.3390/ijms221810068 - 17 Sep 2021

Cited by 8 | Viewed by 3213

Abstract

Human Angiogenin (hANG, or ANG, 14.1 kDa) promotes vessel formation and is also called RNase 5 because it is included in the pancreatic-type ribonuclease (pt-RNase) super-family. Although low, its ribonucleolytic activity is crucial for angiogenesis in tumor tissues but also in the physiological development of the Central Nervous System (CNS) neuronal progenitors. Nevertheless, some ANG variants are involved in both neurodegenerative Parkinson disease (PD) and Amyotrophic Lateral Sclerosis (ALS). Notably, some pt-RNases acquire new biological functions upon oligomerization. Considering neurodegenerative diseases correlation with massive protein aggregation, we analyzed the aggregation propensity of ANG and of three of its pathogenic variants, namely H13A, S28N, and R121C. We found no massive aggregation, but wt-ANG, as well as S28N and R121C variants, can form an enzymatically active dimer, which is called ANG-D. By contrast, the enzymatically inactive H13A-ANG does not dimerize. Corroborated by a specific cross-linking analysis and by the behavior of H13A-ANG that in turn lacks one of the two His active site residues necessary for pt-RNases to self-associate through the three-dimensional domain swapping (3D-DS), we demonstrate that ANG actually dimerizes through 3D-DS. Then, we deduce by size exclusion chromatography (SEC) and modeling that ANG-D forms through the swapping of ANG N-termini. In light of these novelties, we can expect future investigations to unveil other ANG determinants possibly related with the onset and/or development of neurodegenerative pathologies. Full article

(This article belongs to the Special Issue Protein Oligomerization)

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25 pages, 3344 KiB

Open AccessArticle

Structural Features and Toxicity of α-Synuclein Oligomers Grown in the Presence of DOPAC

by Luana Palazzi, Benedetta Fongaro, Manuela Leri, Laura Acquasaliente, Massimo Stefani, Monica Bucciantini and Patrizia Polverino de Laureto

Int. J. Mol. Sci. 2021, 22(11), 6008; https://doi.org/10.3390/ijms22116008 - 2 Jun 2021

Cited by 14 | Viewed by 3982

Abstract

The interplay between α-synuclein and dopamine derivatives is associated with oxidative stress-dependent neurodegeneration in Parkinson’s disease (PD). The formation in the dopaminergic neurons of intraneuronal inclusions containing aggregates of α-synuclein is a typical hallmark of PD. Even though the biochemical events underlying the aberrant aggregation of α-synuclein are not completely understood, strong evidence correlates this process with the levels of dopamine metabolites. In vitro, 3,4-dihydroxyphenylacetaldehyde (DOPAL) and the other two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylethanol (DOPET), share the property to inhibit the growth of mature amyloid fibrils of α-synuclein. Although this effect occurs with the formation of differently toxic products, the molecular basis of this inhibition is still unclear. Here, we provide information on the effect of DOPAC on the aggregation properties of α-synuclein and its ability to interact with membranes. DOPAC inhibits α-synuclein aggregation, stabilizing monomer and inducing the formation of dimers and trimers. DOPAC-induced oligomers did not undergo conformational transition in the presence of membranes, and penetrated the cell, where they triggered autophagic processes. Cellular assays showed that DOPAC reduced cytotoxicity and ROS production induced by α-synuclein aggregates. Our findings show that the early radicals resulting from DOPAC autoxidation produced covalent modifications of the protein, which were not by themselves a primary cause of either fibrillation or membrane binding inhibition. These findings are discussed in the light of the potential mechanism of DOPAC protection against the toxicity of α-synuclein aggregates to better understand protein and catecholamine biology and to eventually suggest a scaffold that can help in the design of candidate molecules able to interfere in α-synuclein aggregation. Full article

(This article belongs to the Special Issue Protein Oligomerization)

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16 pages, 1888 KiB

Open AccessArticle

NMR Characterization of Angiogenin Variants and tRNA^Ala Products Impacting Aberrant Protein Oligomerization

by Andrea Fagagnini, Miguel Garavís, Irene Gómez-Pinto, Sabrina Fasoli, Giovanni Gotte and Douglas V. Laurents

Int. J. Mol. Sci. 2021, 22(3), 1439; https://doi.org/10.3390/ijms22031439 - 1 Feb 2021

Cited by 5 | Viewed by 3012

Abstract

Protein oligomerization is key to countless physiological processes, but also to abnormal amyloid conformations implicated in over 25 mortal human diseases. Human Angiogenin (h-ANG), a ribonuclease A family member, produces RNA fragments that regulate ribosome formation, the creation of new blood vessels and stress granule function. Too little h-ANG activity leads to abnormal protein oligomerization, resulting in Amyotrophic Lateral Sclerosis (ALS) or Parkinson’s disease. While a score of disease linked h-ANG mutants has been studied by X-ray diffraction, some elude crystallization. There is also a debate regarding the structure that RNA fragments adopt after cleavage by h-ANG. Here, to better understand the beginning of the process that leads to aberrant protein oligomerization, the solution secondary structure and residue-level dynamics of WT h-ANG and two mutants i.e., H13A and R121C, are characterized by multidimensional heteronuclear NMR spectroscopy under near-physiological conditions. All three variants are found to adopt well folded and highly rigid structures in the solution, although the elements of secondary structure are somewhat shorter than those observed in crystallography studies. R121C alters the environment of nearby residues only. By contrast, the mutation H13A affects local residues as well as nearby active site residues K40 and H114. The conformation characterization by CD and 1D ¹H NMR spectroscopies of tRNA^Ala before and after h-ANG cleavage reveals a retention of the duplex structure and little or no G-quadruplex formation. Full article

(This article belongs to the Special Issue Protein Oligomerization)

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21 pages, 5169 KiB

Open AccessArticle

Soluble Prion Peptide 107–120 Protects Neuroblastoma SH-SY5Y Cells against Oligomers Associated with Alzheimer’s Disease

by Elham Rezvani Boroujeni, Seyed Masoud Hosseini, Giulia Fani, Cristina Cecchi and Fabrizio Chiti

Int. J. Mol. Sci. 2020, 21(19), 7273; https://doi.org/10.3390/ijms21197273 - 1 Oct 2020

Cited by 5 | Viewed by 3397

Abstract

Alzheimer’s disease (AD) is the most prevalent form of dementia and soluble amyloid β (Aβ) oligomers are thought to play a critical role in AD pathogenesis. Cellular prion protein (PrP^C) is a high-affinity receptor for Aβ oligomers and mediates some of their toxic effects. The N-terminal region of PrP^C can interact with Aβ, particularly the region encompassing residues 95–110. In this study, we identified a soluble and unstructured prion-derived peptide (PrP_107–120) that is external to this region of the sequence and was found to successfully reduce the mitochondrial impairment, intracellular ROS generation and cytosolic Ca²⁺ uptake induced by oligomeric Aβ₄₂ ADDLs in neuroblastoma SH-SY5Y cells. PrP_107–120 was also found to rescue SH-SY5Y cells from Aβ₄₂ ADDL internalization. The peptide did not change the structure and aggregation pathway of Aβ₄₂ ADDLs, did not show co-localization with Aβ₄₂ ADDLs in the cells and showed a partial colocalization with the endogenous cellular PrP^C. As a sequence region that is not involved in Aβ binding but in PrP self-recognition, the peptide was suggested to protect against the toxicity of Aβ₄₂ oligomers by interfering with cellular PrP^C and/or activating a signaling that protected the cells. These results strongly suggest that PrP_107–120 has therapeutic potential for AD. Full article

(This article belongs to the Special Issue Protein Oligomerization)

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Review

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24 pages, 29758 KiB

Open AccessReview

Structure, Oligomerization and Activity Modulation in N-Ribohydrolases

by Massimo Degano

Int. J. Mol. Sci. 2022, 23(5), 2576; https://doi.org/10.3390/ijms23052576 - 25 Feb 2022

Cited by 8 | Viewed by 2631

Abstract

Enzymes catalyzing the hydrolysis of the N-glycosidic bond in nucleosides and other ribosides (N-ribohydrolases, NHs) with diverse substrate specificities are found in all kingdoms of life. While the overall NH fold is highly conserved, limited substitutions and insertions can account for differences in substrate selection, catalytic efficiency, and distinct structural features. The NH structural module is also employed in monomeric proteins devoid of enzymatic activity with different physiological roles. The homo-oligomeric quaternary structure of active NHs parallels the different catalytic strategies used by each isozyme, while providing a buttressing effect to maintain the active site geometry and allow the conformational changes required for catalysis. The unique features of the NH catalytic strategy and structure make these proteins attractive targets for diverse therapeutic goals in different diseases. Full article

(This article belongs to the Special Issue Protein Oligomerization)

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20 pages, 1349 KiB

Open AccessReview

Modeling and Structure Determination of Homo-Oligomeric Proteins: An Overview of Challenges and Current Approaches

by Aljaž Gaber and Miha Pavšič

Int. J. Mol. Sci. 2021, 22(16), 9081; https://doi.org/10.3390/ijms22169081 - 23 Aug 2021

Cited by 16 | Viewed by 8128

Abstract

Protein homo-oligomerization is a very common phenomenon, and approximately half of proteins form homo-oligomeric assemblies composed of identical subunits. The vast majority of such assemblies possess internal symmetry which can be either exploited to help or poses challenges during structure determination. Moreover, aspects of symmetry are critical in the modeling of protein homo-oligomers either by docking or by homology-based approaches. Here, we first provide a brief overview of the nature of protein homo-oligomerization. Next, we describe how the symmetry of homo-oligomers is addressed by crystallographic and non-crystallographic symmetry operations, and how biologically relevant intermolecular interactions can be deciphered from the ordered array of molecules within protein crystals. Additionally, we describe the most important aspects of protein homo-oligomerization in structure determination by NMR. Finally, we give an overview of approaches aimed at modeling homo-oligomers using computational methods that specifically address their internal symmetry and allow the incorporation of other experimental data as spatial restraints to achieve higher model reliability. Full article

(This article belongs to the Special Issue Protein Oligomerization)

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13 pages, 1530 KiB

Open AccessReview

Fatal Attraction: The Case of Toxic Soluble Dimers of Truncated PQBP-1 Mutants in X-Linked Intellectual Disability

by Yu Wai Chen and Shah Kamranur Rahman

Int. J. Mol. Sci. 2021, 22(5), 2240; https://doi.org/10.3390/ijms22052240 - 24 Feb 2021

Cited by 1 | Viewed by 2408

Abstract

The frameshift mutants K192S^fs*7 and R153S^fs*41, of the polyglutamine tract-binding protein 1 (PQBP-1), are stable intrinsically disordered proteins (IDPs). They are each associated with the severe cognitive disorder known as the Renpenning syndrome, a form of X-linked intellectual disability (XLID). Relative to the monomeric wild-type protein, these mutants are dimeric, contain more folded contents, and have higher thermal stabilities. Comparisons can be drawn to the toxic oligomerisation in the “conformational diseases”, which collectively describe medical conditions involving a substantial protein structural transition in the pathogenic mechanism. At the molecular level, the end state of these diseases is often cytotoxic protein aggregation. The conformational disease proteins contain varying extents of intrinsic disorder, and the consensus pathogenesis includes an early oligomer formation. We reviewed the experimental characterisation of the toxic oligomers in representative cases. PQBP-1 mutant dimerisation was then compared to the oligomerisation of the conformational disease proteins. The PQBP-1 mutants are unique in behaving as stable soluble dimers, which do not further develop into higher oligomers or aggregates. The toxicity of the PQBP-1 mutant dimers lies in the native functions (in transcription regulation and possibly, RNA splicing) being compromised, rather than proceeding to aggregation. Other examples of stable IDP dimers were discussed and we speculated on the roles of IDP dimerisation in protein evolution. Full article

(This article belongs to the Special Issue Protein Oligomerization)

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