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Protein Oligomerization 2.0

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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 (16 March 2023) | Viewed by 7261

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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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Dr. Marta Menegazzi

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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
Special Issues, Collections and Topics in MDPI journals

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.

Dr. Giovanni Gotte
Dr. Marta Menegazzi
Guest Editors

Manuscript Submission Information

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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

Published Papers (4 papers)

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Research

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13 pages, 4473 KiB

Open AccessArticle

Anomalous Oligomerization Behavior of E. coli Aquaporin Z in Detergent and in Nanodiscs

by Wahyu Surya, Clare Pei Yii Yong, Anu Tyagi, Shashi Bhushan and Jaume Torres

Int. J. Mol. Sci. 2023, 24(9), 8098; https://doi.org/10.3390/ijms24098098 - 30 Apr 2023

Viewed by 1577

Abstract

Aquaporins are tetrameric integral membrane proteins that act as water channels, and can also permeabilize membranes to other solutes. The monomer appears to be the functional form despite all aquaporins being organized as tetramers, which therefore must provide a clear functional advantage. In addition to this quaternary organization, some aquaporins can act as adhesion molecules in membrane junctions, when tetramers located in opposing membranes interact via their extracellular domains. These stacked forms have been observed in a range of aquaporins, whether using lipidic membrane environments, in electron crystallography, or using detergent micelles, in single-particle cryo-electron microscopy (cryo-EM). In the latter technique, structural studies can be performed when the aquaporin is reconstituted into nanodiscs of lipids that are surrounded by a protein scaffold. During attempts to study E. coli Aquaporin Z (AqpZ), we have found that in some conditions these nanodiscs tend to form filaments that appear to be either thicker head-to-tail or thinner side-to-side stacks of nanodiscs. Nanodisc oligomerization was observed using orthogonal analytical techniques analytical ultra-centrifugation and mass photometry, although the nature of the oligomers (head-to-tail or side-to-side) could not be determined. Using the latter technique, the AqpZ tetramer itself formed oligomers of increasing size when solubilized only in detergent, which is consistent with multiple stacking of AqpZ tetramers. We observed images consistent with both of these filaments in negative staining EM conditions, but only thicker filaments in cryo-EM conditions. We hypothesize that the apparent nanodisc side-to-side arrangement that can only be visualized in negative staining conditions is related to artifacts due to the sample preparation. Filaments of any kind were not observed in EM when nanodiscs did not contain AqpZ, or after addition of detergent into the nanodisc cryo-EM preparation, at concentrations that did not disrupt nanodisc formation. To our knowledge, these filaments have not been observed in nanodiscs preparations of other membrane proteins. AqpZ, like other aquaporins has a charge asymmetry between the cytoplasmic (more positive) and the extracellular sides, which may explain the likely head-to-tail stacking observed, both in nanodisc preparations and also in detergent micelles. Full article

(This article belongs to the Special Issue Protein Oligomerization 2.0)

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13 pages, 2255 KiB

Open AccessArticle

GxxxG Motif Stabilize Ion-Channel like Pores through C_α―H···O Interaction in Aβ (1-40)

by Carola Rando, Giuseppe Grasso, Dibakar Sarkar, Michele Francesco Maria Sciacca, Lorena Maria Cucci, Alessia Cosentino, Giuseppe Forte, Martina Pannuzzo, Cristina Satriano, Anirban Bhunia and Carmelo La Rosa

Int. J. Mol. Sci. 2023, 24(3), 2192; https://doi.org/10.3390/ijms24032192 - 22 Jan 2023

Cited by 4 | Viewed by 1487

Abstract

Aβ (1-40) can transfer from the aqueous phase to the bilayer and thus form stable ion-channel-like pores where the protein has alpha-helical conformation. The stability of the pores is due to the presence of the GXXXG motif. It has been reported that these ion-channel-like pores are stabilized by a Cα―H···O hydrogen bond that is established between a glycine of the GXXXG sequence of an alpha-helix and another amino acid of a vicinal alpha-helix. However, conflicting data are reported in the literature. Some authors have suggested that hydrogen bonding does not have a stabilizing function. Here we synthesized pentapeptides having a GXXXG motif to explore its role in pore stability. We used molecular dynamics simulations, quantum mechanics, and experimental biophysical techniques to determine whether hydrogen bonding was formed and had a stabilizing function in ion-channel-like structures. Starting from our previous molecular dynamics data, molecular quantum mechanics simulations, and ATR data showed that a stable ion-channel-like pore formed and a band centered at 2910 cm⁻¹ was attributed to the interaction between Gly 7 of an alpha-helix and Asp 23 of a vicinal alpha-helix. Full article

(This article belongs to the Special Issue Protein Oligomerization 2.0)

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17 pages, 6018 KiB

Open AccessArticle

Alphafold Predictions Provide Insights into the Structural Features of the Functional Oligomers of All Members of the KCTD Family

by Luciana Esposito, Nicole Balasco and Luigi Vitagliano

Int. J. Mol. Sci. 2022, 23(21), 13346; https://doi.org/10.3390/ijms232113346 - 01 Nov 2022

Cited by 6 | Viewed by 1663

Abstract

Oligomerization endows proteins with some key properties such as extra-stabilization, long-range allosteric regulation(s), and partnerships not accessible to their monomeric counterparts. How oligomerization is achieved and preserved during evolution is a subject of remarkable scientific relevance. By exploiting the abilities of the machine-learning algorithms implemented in AlphaFold (AF) in predicting protein structures, herein, we report a comprehensive analysis of the structural states of functional oligomers of all members of the KCTD protein family. Interestingly, our approach led to the identification of reliable three-dimensional models for the pentameric states of KCNRG, KCTD6, KCTD4, KCTD7, KCTD9, and KCTD14 and possibly for KCTD11 and KCTD21 that are involved in key biological processes and that were previously uncharacterized from a structural point of view. Although for most of these proteins, the CTD domains lack any sequence similarity, they share some important structural features, such as a propeller-like structure with a central cavity delimited by five exposed and regular β-strands. Moreover, the structure of the related proteins KCTD7 and KCTD14, although pentameric, appears to be characterized by a different organization of the CTD region, with the five chains forming a circle-like structure with a large cavity. Our predictions also suggest that other members of the family, such as KCTD10, KCTD13, and TNFAIP1, present a strong propensity to assume dimeric states. Although the structures of the functional oligomers reported herein represent models that require additional validations, they provide a consistent and global view of KCTD protein oligomerization. Full article

(This article belongs to the Special Issue Protein Oligomerization 2.0)

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Review

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19 pages, 1690 KiB

Open AccessReview

The Role of Proteolysis in Amyloidosis

by Laura Acquasaliente and Vincenzo De Filippis

Int. J. Mol. Sci. 2023, 24(1), 699; https://doi.org/10.3390/ijms24010699 - 31 Dec 2022

Cited by 6 | Viewed by 2193

Abstract

Amyloidoses are a group of diseases associated with deposits of amyloid fibrils in different tissues. So far, 36 different types of amyloidosis are known, each due to the misfolding and accumulation of a specific protein. Amyloid deposits can be found in several organs, including the heart, brain, kidneys, and spleen, and can affect single or multiple organs. Generally, amyloid-forming proteins become prone to aggregate due to genetic mutations, acquired environmental factors, excessive concentration, or post-translational modifications. Interestingly, amyloid aggregates are often composed of proteolytic fragments, derived from the degradation of precursor proteins by yet unidentified proteases, which display higher amyloidogenic tendency compared to precursor proteins, thus representing an important mechanism in the onset of amyloid-based diseases. In the present review, we summarize the current knowledge on the proteolytic susceptibility of three of the main human amyloidogenic proteins, i.e., transthyretin, β-amyloid precursor protein, and α-synuclein, in the onset of amyloidosis. We also highlight the role that proteolytic enzymes can play in the crosstalk between intestinal inflammation and amyloid-based diseases. Full article

(This article belongs to the Special Issue Protein Oligomerization 2.0)

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