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Structural aspects of the human small heat shock proteins related to their functional activities.

ABSTRACT: Small heat shock proteins function as chaperones by binding unfolding substrate proteins in an ATP-independent manner to keep them in a folding-competent state and to prevent irreversible aggregation. They play crucial roles in diseases that are characterized by protein aggregation, such as neurodegenerative and neuromuscular diseases, but are also involved in cataract, cancer, and congenital disorders. For this reason, these proteins are interesting therapeutic targets for finding molecules that could affect the chaperone activity or compensate specific mutations. This review will give an overview of the available knowledge on the structural complexity of human small heat shock proteins, which may aid in the search for such therapeutic molecules.

SUBMITTER: Boelens WC

PROVIDER: S-EPMC7332592 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Structural aspects of the human small heat shock proteins related to their functional activities.

Boelens Wilbert C WC

Cell stress & chaperones 20200406 4

Small heat shock proteins function as chaperones by binding unfolding substrate proteins in an ATP-independent manner to keep them in a folding-competent state and to prevent irreversible aggregation. They play crucial roles in diseases that are characterized by protein aggregation, such as neurodegenerative and neuromuscular diseases, but are also involved in cataract, cancer, and congenital disorders. For this reason, these proteins are interesting therapeutic targets for finding molecules tha ...[more]

PMID: 32253739

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Project description:Small heat shock proteins (sHsps) are a ubiquitous part of the machinery that maintains cellular protein homeostasis by acting as molecular chaperones. sHsps bind to and prevent the aggregation of partially folded substrate proteins in an ATP-independent manner. sHsps are dynamic, forming an ensemble of structures from dimers to large oligomers through concentration-dependent equilibrium dissociation. Based on structural studies and mutagenesis experiments, it is proposed that the dimer is the smallest active chaperone unit, while larger oligomers may act as storage depots for sHsps or play additional roles in chaperone function. The complexity and dynamic nature of their structural organization has made elucidation of their chaperone function challenging. HspB1 and HspB5 are two canonical human sHsps that vary in sequence and are expressed in a wide variety of tissues. In order to determine the role of the dimer in chaperone activity, glutathione-S-transferase (GST) was genetically linked as a fusion protein to the N-terminus regions of both HspB1 and HspB5 (also known as Hsp27 and ?B-crystallin, respectively) proteins in order to constrain oligomer formation of HspB1 and HspB5, by using GST, since it readily forms a dimeric structure. We monitored the chaperone activity of these fusion proteins, which suggest they primarily form dimers and monomers and function as active molecular chaperones. Furthermore, the two different fusion proteins exhibit different chaperone activity for two model substrate proteins, citrate synthase (CS) and malate dehydrogenase (MDH). GST-HspB1 prevents more aggregation of MDH compared to GST-HspB5 and wild type HspB1. However, when CS is the substrate, both GST-HspB1 and GST-HspB5 are equally effective chaperones. Furthermore, wild type proteins do not display equal activity toward the substrates, suggesting that each sHsp exhibits different substrate specificity. Thus, substrate specificity, as described here for full-length GST fusion proteins with MDH and CS, is modulated by both sHsp oligomeric conformation and by variations of sHsp sequences.

Dataset Information

Structural aspects of the human small heat shock proteins related to their functional activities.

Publications

Structural aspects of the human small heat shock proteins related to their functional activities.

Similar Datasets

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