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

Wilbert C Boelens

doi:10.1007/s12192-020-01093-1

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.

Highlights

Human small heat shock proteinsThe human genome encodes ten small heat shock proteins, called HSPB1 through HSPB10, some of which are ubiquitously expressed, while others show tissue specificity
Human small heat shock proteins (sHSPs) have a remarkable degree of structural variation, ranging from dimers (HSPB6, HSPB7, and HSPB8) to heterotetramers with a well-defined subunit ratio (HSPB2/B3) to polydisperse co-assembling oligomeric
These ten human sHSPs can be considered as paralogous proteins, having originated by gene duplications from a common ancestral gene and are likely to be present in all mammals (Hochberg et al 2018)

Summary

Human small heat shock proteins

The human genome encodes ten small heat shock proteins (sHSPs), called HSPB1 through HSPB10, some of which are ubiquitously expressed, while others show tissue specificity. They are key components of the cellular protein quality control system, acting as the first line of defense against conditions that affect proteome stability. The defining feature of the sHSP family is a characteristic stretch of 80 amino acid residues, the so-called α-crystallin domain (ACD). This domain is both necessary and sufficient for the formation of dimers, the fundamental building block of the oligomeric structures that often are formed by sHSPs. The ACD is flanked by a less conserved N-terminal domain and a variable C-terminal extension, which both play a crucial role in oligomerization. Human sHSPs have a remarkable degree of structural variation, ranging from dimers (HSPB6, HSPB7, and HSPB8) to heterotetramers with a well-defined subunit ratio (HSPB2/B3) to polydisperse co-assembling oligomeric

Expression of the human sHSPs

Large oligomers

Structure of human sHSPs

Influence of stress conditions on the oligomeric structure of human sHSPs

Influence of disease mutations on the structure of sHSPs