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Special Issue "Structure and Function of Small Heat Shock Proteins"

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

Deadline for manuscript submissions: 31 March 2021.

Special Issue Editor

Prof. Dr. Nikolai B. Gusev
Website
Guest Editor
Department of Biochemistry, School of Biology, Moscow State University, Moscow 119991, Russian Federation
Interests: small heat shock proteins; postranslational modifications; protein-protein interactions; heterooligomeric complexes; congenital diseases

Special Issue Information

Dear Colleagues,

Small heat shock proteins form a very large and diverse family of proteins ubiquitously expressed in viruses, archaea, bacteria, plants and animals. Together with other chaperones small heat shock proteins control proper protein folding and prevent accumulation of denatured proteins in the cells. As a rule several isoforms of small heat shock proteins are simultaneously expressed in the cell and these isoforms can form both homo- and heterooligomeric complexes and can interact with other chaperones providing effective protein quality control. Small heat shock proteins undergo different posttranslational modifications that affect their structure, function and interaction with partner proteins. Small heat shock proteins are involved in many intra- and extracellular processes including control of redox state, proteasomal and autosomal protein degradation, apoptosis, regulation of cytoskeleton and muscle contraction, immunological response and many others. Mutations of small heat shock proteins correlate with many congenital disorders including cataract, different neurodegenerative diseases, cardiomyopathies and myopathies. Moreover, small heat shock proteins can be used as markers of different human diseases including cancer.

The goal of this special issue is to present the current knowledge on the structure and function of small heat shock proteins and their probable involvement in different cellular processes and human diseases.

We look forward to your contributions.

Prof. Dr. Nikolai B. Gusev
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • small heat shock proteins
  • posttranslational modifications
  • monomeric and oligomeric structure
  • heterooligomers
  • chaperone-like activity
  • redox state regulation
  • autophagy
  • apoptosis
  • congenital diseases

Published Papers (6 papers)

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Research

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Open AccessArticle
Chaperone-Assisted Mitotic Actin Remodeling by BAG3 and HSPB8 Involves the Deacetylase HDAC6 and Its Substrate Cortactin
Int. J. Mol. Sci. 2021, 22(1), 142; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010142 - 25 Dec 2020
Abstract
The fidelity of actin dynamics relies on protein quality control, but the underlying molecular mechanisms are poorly defined. During mitosis, the cochaperone BCL2-associated athanogene 3 (BAG3) modulates cell rounding, cortex stability, spindle orientation, and chromosome segregation. Mitotic BAG3 shows enhanced interactions with its [...] Read more.
The fidelity of actin dynamics relies on protein quality control, but the underlying molecular mechanisms are poorly defined. During mitosis, the cochaperone BCL2-associated athanogene 3 (BAG3) modulates cell rounding, cortex stability, spindle orientation, and chromosome segregation. Mitotic BAG3 shows enhanced interactions with its preferred chaperone partner HSPB8, the autophagic adaptor p62/SQSTM1, and HDAC6, a deacetylase with cytoskeletal substrates. Here, we show that depletion of BAG3, HSPB8, or p62/SQSTM1 can recapitulate the same inhibition of mitotic cell rounding. Moreover, depletion of either of these proteins also interfered with the dynamic of the subcortical actin cloud that contributes to spindle positioning. These phenotypes were corrected by drugs that limit the Arp2/3 complex or HDAC6 activity, arguing for a role for BAG3 in tuning branched actin network assembly. Mechanistically, we found that cortactin acetylation/deacetylation is mitotically regulated and is correlated with a reduced association of cortactin with HDAC6 in situ. Remarkably, BAG3 depletion hindered the mitotic decrease in cortactin–HDAC6 association. Furthermore, expression of an acetyl-mimic cortactin mutant in BAG3-depleted cells normalized mitotic cell rounding and the subcortical actin cloud organization. Together, these results reinforce a BAG3′s function for accurate mitotic actin remodeling, via tuning cortactin and HDAC6 spatial dynamics. Full article
(This article belongs to the Special Issue Structure and Function of Small Heat Shock Proteins)
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Open AccessArticle
Origin and Evolution of the Human Bcl2-Associated Athanogene-1 (BAG-1)
Int. J. Mol. Sci. 2020, 21(24), 9701; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249701 - 18 Dec 2020
Abstract
Molecular chaperones, particularly the 70-kDa heat shock proteins (Hsp70s), are key orchestrators of the cellular stress response. To perform their critical functions, Hsp70s require the presence of specific co-chaperones, which include nucleotide exchange factors containing the BCL2-associated athanogene (BAG) domain. BAG-1 is one [...] Read more.
Molecular chaperones, particularly the 70-kDa heat shock proteins (Hsp70s), are key orchestrators of the cellular stress response. To perform their critical functions, Hsp70s require the presence of specific co-chaperones, which include nucleotide exchange factors containing the BCL2-associated athanogene (BAG) domain. BAG-1 is one of these proteins that function in a wide range of cellular processes, including apoptosis, protein refolding, and degradation, as well as tumorigenesis. However, the origin of BAG-1 proteins and their evolution between and within species are mostly uncharacterized. This report investigated the macro- and micro-evolution of BAG-1 using orthologous sequences and single nucleotide polymorphisms (SNPs) to elucidate the evolution and understand how natural variation affects the cellular stress response. We first collected and analyzed several BAG-1 sequences across animals, plants, and fungi; mapped intron positions and phases; reconstructed phylogeny; and analyzed protein characteristics. These data indicated that BAG-1 originated before the animals, plants, and fungi split, yet most extant fungal species have lost BAG-1. Furthermore, although BAG-1’s structure has remained relatively conserved, kingdom-specific conserved differences exist at sites of known function, suggesting functional specialization within each kingdom. We then analyzed SNPs from the 1000 genomes database to determine the evolutionary patterns within humans. These analyses revealed that the SNP density is unequally distributed within the BAG1 gene, and the ratio of non-synonymous/synonymous SNPs is significantly higher than 1 in the BAG domain region, which is an indication of positive selection. To further explore this notion, we performed several biochemical assays and found that only one out of five mutations tested altered the major co-chaperone properties of BAG-1. These data collectively suggest that although the co-chaperone functions of BAG-1 are highly conserved and can probably tolerate several radical mutations, BAG-1 might have acquired specialized and potentially unexplored functions during the evolutionary process. Full article
(This article belongs to the Special Issue Structure and Function of Small Heat Shock Proteins)
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Open AccessArticle
Chaperone-Like Activity of HSPB5: The Effects of Quaternary Structure Dynamics and Crowding
Int. J. Mol. Sci. 2020, 21(14), 4940; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144940 - 13 Jul 2020
Abstract
Small heat-shock proteins (sHSPs) are ATP-independent molecular chaperones that interact with partially unfolded proteins, preventing their aberrant aggregation, thereby exhibiting a chaperone-like activity. Dynamics of the quaternary structure plays an important role in the chaperone-like activity of sHSPs. However, relationship between the dynamic [...] Read more.
Small heat-shock proteins (sHSPs) are ATP-independent molecular chaperones that interact with partially unfolded proteins, preventing their aberrant aggregation, thereby exhibiting a chaperone-like activity. Dynamics of the quaternary structure plays an important role in the chaperone-like activity of sHSPs. However, relationship between the dynamic structure of sHSPs and their chaperone-like activity remains insufficiently characterized. Many factors (temperature, ions, a target protein, crowding etc.) affect the structure and activity of sHSPs. The least studied is an effect of crowding on sHSPs activity. In this work the chaperone-like activity of HSPB5 was quantitatively characterized by dynamic light scattering using two test systems, namely test systems based on heat-induced aggregation of muscle glycogen phosphorylase b (Phb) at 48 °C and dithiothreitol-induced aggregation of α-lactalbumin at 37 °C. Analytical ultracentrifugation was used to control the oligomeric state of HSPB5 and target proteins. The possible anti-aggregation functioning of suboligomeric forms of HSPB5 is discussed. The effect of crowding on HSPB5 anti-aggregation activity was characterized using Phb as a target protein. The duration of the nucleation stage was shown to decrease with simultaneous increase in the relative rate of aggregation of Phb in the presence of HSPB5 under crowded conditions. Crowding may subtly modulate sHSPs activity. Full article
(This article belongs to the Special Issue Structure and Function of Small Heat Shock Proteins)
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Open AccessArticle
The Heterooligomerization of Human Small Heat Shock Proteins Is Controlled by Conserved Motif Located in the N-Terminal Domain
Int. J. Mol. Sci. 2020, 21(12), 4248; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124248 - 15 Jun 2020
Cited by 2
Abstract
Ubiquitously expressed human small heat shock proteins (sHsps) HspB1, HspB5, HspB6 and HspB8 contain a conserved motif (S/G)RLFD in their N-terminal domain. For each of them, we prepared mutants with a replacement of the conserved R by A (R/A mutants) and a complete [...] Read more.
Ubiquitously expressed human small heat shock proteins (sHsps) HspB1, HspB5, HspB6 and HspB8 contain a conserved motif (S/G)RLFD in their N-terminal domain. For each of them, we prepared mutants with a replacement of the conserved R by A (R/A mutants) and a complete deletion of the pentapeptide (Δ mutants) and analyzed their heterooligomerization with other wild-type (WT) human sHsps. We found that WT HspB1 and HspB5 formed heterooligomers with HspB6 only upon heating. In contrast, both HspB1 mutants interacted with WT HspB6 even at low temperature. HspB1/HspB6 heterooligomers revealed a broad size distribution with equimolar ratio suggestive of heterodimers as building blocks, while HspB5/HspB6 heterooligomers had an approximate 2:1 ratio. In contrast, R/A or Δ mutants of HspB6, when mixed with either HspB1 or HspB5, resulted in heterooligomers with a highly variable molar ratio and a decreased HspB6 incorporation. No heterooligomerization of HspB8 or its mutants with either HspB1 or HspB5 could be detected. Finally, R/A or Δ mutations had no effect on heterooligomerization of HspB1 and HspB5 as analyzed by ion exchange chromatography. We conclude that the conserved N-terminal motif plays an important role in heterooligomer formation, as especially pronounced in HspB6 lacking the C-terminal IXI motif. Full article
(This article belongs to the Special Issue Structure and Function of Small Heat Shock Proteins)
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Review

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Open AccessReview
Small Heat Shock Proteins in Cancers: Functions and Therapeutic Potential for Cancer Therapy
Int. J. Mol. Sci. 2020, 21(18), 6611; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186611 - 10 Sep 2020
Cited by 1
Abstract
Small heat shock proteins (sHSPs) are ubiquitous ATP-independent chaperones that play essential roles in response to cellular stresses and protein homeostasis. Investigations of sHSPs reveal that sHSPs are ubiquitously expressed in numerous types of tumors, and their expression is closely associated with cancer [...] Read more.
Small heat shock proteins (sHSPs) are ubiquitous ATP-independent chaperones that play essential roles in response to cellular stresses and protein homeostasis. Investigations of sHSPs reveal that sHSPs are ubiquitously expressed in numerous types of tumors, and their expression is closely associated with cancer progression. sHSPs have been suggested to control a diverse range of cancer functions, including tumorigenesis, cell growth, apoptosis, metastasis, and chemoresistance, as well as regulation of cancer stem cell properties. Recent advances in the field indicate that some sHSPs have been validated as a powerful target in cancer therapy. In this review, we present and highlight current understanding, recent progress, and future challenges of sHSPs in cancer development and therapy. Full article
(This article belongs to the Special Issue Structure and Function of Small Heat Shock Proteins)
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Open AccessReview
Proteinaceous Transformers: Structural and Functional Variability of Human sHsps
Int. J. Mol. Sci. 2020, 21(15), 5448; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155448 - 30 Jul 2020
Abstract
The proteostasis network allows organisms to support and regulate the life cycle of proteins. Especially regarding stress, molecular chaperones represent the main players within this network. Small heat shock proteins (sHsps) are a diverse family of ATP-independent molecular chaperones acting as the first [...] Read more.
The proteostasis network allows organisms to support and regulate the life cycle of proteins. Especially regarding stress, molecular chaperones represent the main players within this network. Small heat shock proteins (sHsps) are a diverse family of ATP-independent molecular chaperones acting as the first line of defense in many stress situations. Thereby, the promiscuous interaction of sHsps with substrate proteins results in complexes from which the substrates can be refolded by ATP-dependent chaperones. Particularly in vertebrates, sHsps are linked to a broad variety of diseases and are needed to maintain the refractive index of the eye lens. A striking key characteristic of sHsps is their existence in ensembles of oligomers with varying numbers of subunits. The respective dynamics of these molecules allow the exchange of subunits and the formation of hetero-oligomers. Additionally, these dynamics are closely linked to the chaperone activity of sHsps. In current models a shift in the equilibrium of the sHsp ensemble allows regulation of the chaperone activity, whereby smaller oligomers are commonly the more active species. Different triggers reversibly change the oligomer equilibrium and regulate the activity of sHsps. However, a finite availability of high-resolution structures of sHsps still limits a detailed mechanistic understanding of their dynamics and the correlating recognition of substrate proteins. Here we summarize recent advances in understanding the structural and functional relationships of human sHsps with a focus on the eye-lens αA- and αB-crystallins. Full article
(This article belongs to the Special Issue Structure and Function of Small Heat Shock Proteins)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Alpha-crystallin: Is it possible to obtain a 3D reconstructed model of heterogeneous oligomer complexes?

Author: Oxana V. Galzitskaya

Title: Modulation of cortical actin dynamics during mitosis by the chaperone complex BAG3-HSPB8 and p62/SQSTM1

Author: Josée N. Lavoie

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