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Special Issue "Molecular Chaperones: Protein Folding, Proteostasis, and Diseases"

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

Deadline for manuscript submissions: 15 December 2023 | Viewed by 3487

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Prof. Dr. Hideaki Itoh

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Graduate School of Agriculture and Life Sciences, the University of Tokyo, Tokyo 113-0032, Japan
Interests: protein folding; folding diseases; proteostasis; homeostasis; signal transduction
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Dear Colleagues,

Molecular chaperones have been shown to mediate the folding of many post-translational proteins in prokaryotes, archaea, and eukaryotes. The structures of individual molecular chaperones have been elucidated in detail by X-ray crystallography and cryo-electron microscopy. It has also been reported that molecular chaperones are essential for viral replication.

Mammalian molecular chaperones, such as HSP60, HSP70, and HSP90, may exert their physiological functions independently, or co-chaperones may be required. In addition, interactions between multiple chaperones, e.g., HSP70-HOP-HSP90, can lead to new physiological functions.

It has also been reported that incorrect folding of proteins can lead to diseases such as amyloid fibre formation. Furthermore, molecular chaperones have been reported to be involved in various diseases, including various types of cancer. Thus, when homeostasis is not maintained, various diseases can be expected to occur.

This Special Issue welcomes research on the structure and physiological functions of molecular chaperones to clarify how molecular chaperones interact with client proteins, proteostasis in various diseases, etc., and to highlight the impact of molecular chaperones on human health, homeostatic function maintenance, and disease, including the affinity of molecular chaperone inhibitors and various drugs with molecular chaperones and physiological function regulation.

Prof. Dr. Hideaki Itoh
Guest Editor

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Open AccessCommunication

Fusion of Hsp70 to GFP Impairs Its Function and Causes Formation of Misfolded Protein Deposits under Mild Stress in Yeast

Erika V. Grosfeld

Anastasia Yu. Beizer

Alexander A. Dergalev

Michael O. Agaphonov

and

Alexander I. Alexandrov

Int. J. Mol. Sci. 2023, 24(16), 12758; https://doi.org/10.3390/ijms241612758 - 14 Aug 2023

Viewed by 421

Abstract

Protein misfolding is a common feature of aging, various diseases and stresses. Recent work has revealed that misfolded proteins can be gathered into specific compartments, which can limit their deleterious effects. Chaperones play a central role in the formation of these misfolded protein deposits and can also be used to mark them. While studying chimeric yeast Hsp70 (Ssa1-GFP), we discovered that this protein was prone to the formation of large insoluble deposits during growth on non-fermentable carbon sources under mild heat stress. This was mitigated by the addition of antioxidants, suggesting that either Ssa1 itself or some other proteins were affected by oxidative damage. The protein deposits colocalized with a number of other chaperones, as well as model misfolded proteins, and could be disassembled by the Hsp104 chaperone. Notably, the wild-type protein, as well as a fusion protein of Ssa1 to the fluorescent protein Dendra2, were much less prone to forming similar foci, indicating that this phenomenon was related to the perturbation of Ssa1 function by fusion to GFP. This was also confirmed by monitoring Hsp104-GFP aggregates in the presence of known Ssa1 point mutants. Our data indicate that impaired Ssa1 function can favor the formation of large misfolded protein deposits under various conditions. Full article

(This article belongs to the Special Issue Molecular Chaperones: Protein Folding, Proteostasis, and Diseases)

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Open AccessArticle

Identification and Characterization of Proteins That Are Involved in RTP1S-Dependent Transport of Olfactory Receptors

and

Int. J. Mol. Sci. 2023, 24(9), 7829; https://doi.org/10.3390/ijms24097829 - 25 Apr 2023

Viewed by 833

Abstract

Olfaction is mediated via olfactory receptors (ORs) that are expressed on the cilia membrane of olfactory sensory neurons in the olfactory epithelium. The functional expression of most ORs requires the assistance of receptor-transporting proteins (RTPs). We examined the interactome of RTP1S and OR via proximity biotinylation. Deubiquitinating protein VCIP135, the F-actin-capping protein sub-unit alpha-2, and insulin-like growth factor 2 mRNA-binding protein 2 were biotinylated via AirID fused with OR, RTP1S-AirID biotinylated heat shock protein A6 (HSPA6), and double-stranded RNA-binding protein Staufen homolog 2 (STAU2). Co-expression of HSPA6 partially enhanced the surface expression of Olfr544. The surface expression of Olfr544 increased by 50–80%. This effect was also observed when RTP1S was co-expressed. Almost identical results were obtained from the co-expression of STAU2. The interactions of HSPA6 and STAU2 with RTP1S were examined using a NanoBit assay. The results show that the RTP1S N-terminus interacted with the C-terminal domain of HSP6A and the N-terminal domain of STAU2. In contrast, OR did not significantly interact with STAU2 and HSPA6. Thus, HSP6A and STAU2 appear to be involved in the process of OR traffic through interaction with RTP1S. Full article

(This article belongs to the Special Issue Molecular Chaperones: Protein Folding, Proteostasis, and Diseases)

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Open AccessArticle

α-Crystallin Domains of Five Human Small Heat Shock Proteins (sHsps) Differ in Dimer Stabilities and Ability to Incorporate Themselves into Oligomers of Full-Length sHsps

and

Int. J. Mol. Sci. 2023, 24(2), 1085; https://doi.org/10.3390/ijms24021085 - 06 Jan 2023

Cited by 2 | Viewed by 1210

Abstract

The α-crystallin domain (ACD) is the hallmark of a diverse family of small heat shock proteins (sHsps). We investigated some of the ACD properties of five human sHsps as well as their interactions with different full-length sHsps. According to size-exclusion chromatography, at high concentrations, the ACDs of HspB1 (B1ACD), HspB5 (B5ACD) and HspB6 (B6ACD) formed dimers of different stabilities, which, upon dilution, dissociated to monomers to different degrees. Upon dilution, the B1ACD dimers possessed the highest stabilities, and those of B6ACD had the lowest. In striking contrast, the ACDs of HspB7 (B7ACD) and HspB8 (B8ACD) formed monomers in the same concentration range, which indicated the compromised stabilities of their dimer interfaces. B1ACD, B5ACD and B6ACD transiently interacted with full-length HspB1 and HspB5, which are known to form large oligomers, and modulated their oligomerization behavior. The small oligomers formed by the 3D mutant of HspB1 (mimicking phosphorylation at Ser15, Ser78 and Ser82) effectively interacted with B1ACD, B5ACD and B6ACD, incorporating these α-crystallin domains into their structures. The inherently dimeric full-length HspB6 readily formed heterooligomeric complexes with B1ACD and B5ACD. In sharp contrast to the abovementioned ACDs, B7ACD and B8ACD were unable to interact with full-length HspB1, the 3D mutant of HspB1, HspB5 or HspB6. Thus, their high sequence homology notwithstanding, B7ACD and B8ACD differ from the other three ACDs in their inability to form dimers and interact with the full-length small heat shock proteins. Having conservative primary structures and being apparently similar, the ACDs of the different sHsps differ in terms of their dimer stabilities, which can influence the heterooligomerization preferences of sHsps. Full article

(This article belongs to the Special Issue Molecular Chaperones: Protein Folding, Proteostasis, and Diseases)

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Uncovering the Role of Natural and Synthetic Small Molecules in Counteracting the Burden of α-Synuclein Aggregates and Related Toxicity in Different Models of Parkinson’s Disease

Salihu Mohammed

Isabella Russo

and

Ileana Ramazzina

Int. J. Mol. Sci. 2023, 24(17), 13370; https://doi.org/10.3390/ijms241713370 - 29 Aug 2023

Viewed by 408

Abstract

A proteostasis network represents a sophisticated cellular system that controls the whole process which leads to properly folded functional proteins. The imbalance of proteostasis determines a quantitative increase in misfolded proteins prone to aggregation and elicits the onset of different diseases. Among these, Parkinson’s Disease (PD) is a progressive brain disorder characterized by motor and non-motor signs. In PD pathogenesis, alpha-Synuclein (α-Syn) loses its native structure, triggering a polymerization cascade that leads to the formation of toxic inclusions, the PD hallmark. Because molecular chaperones represent a “cellular arsenal” to counteract protein misfolding and aggregation, the modulation of their expression represents a compelling PD therapeutic strategy. This review will discuss evidence concerning the effects of natural and synthetic small molecules in counteracting α-Syn aggregation process and related toxicity, in different in vitro and in vivo PD models. Firstly, the role of small molecules that modulate the function(s) of chaperones will be highlighted. Then, attention will be paid to small molecules that interfere with different steps of the protein-aggregation process. This overview would stimulate in-depth research on already-known small molecules or the development of new ones, with the aim of developing drugs that are able to modify the progression of the disease. Full article

(This article belongs to the Special Issue Molecular Chaperones: Protein Folding, Proteostasis, and Diseases)

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Special Issue "Molecular Chaperones: Protein Folding, Proteostasis, and Diseases"

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