The Role of Intrinsically Disordered Regions in the Structure and Functioning of Small Heat Shock Proteins

Abstract

Small heat shock proteins (sHsp) form a large ubiquitous family of proteins expressed in all phyla of living organisms. The members of this family have low molecular masses (13-43 kDa) and contain a conservative α-crystallin domain. This domain (about 90 residues) consists of several β-strands forming two β-sheets packed in immunoglobulinlike manner. The α-crystallin domain plays an important role in formation of stable sHsp dimers, which are the building blocks of the large sHsp oligomers. A large N-terminal domain and a short C-terminal extension flank the α-crystallin domain. Both the N-terminal domain and the C-terminal extension are flexible, susceptible to proteolysis, prone to posttranslational modifications, and are predominantly intrinsically disordered. Differently oriented N-terminal domains interact with each other, with the core α-crystallin domain of the same or neighboring dimers and play important role in formation of large sHsp oligomers. Phosphorylation of certain sites in the N-terminal domain affects the sHsp quaternary structure, the sHsp interaction with target proteins and the sHsp chaperone-like activity. The C-terminal extension often carrying the conservative tripeptide (I/V/L)-X-(I/V/L) is capable of binding to a hydrophobic groove on the surface of the core α-crystallin domain of neighboring dimer, thus affecting the plasticity and the overall structure of sHsp oligomers. The Cterminal extension interacts with target proteins and affects their interaction with the α-crystallin domain increasing solubility of the complexes formed by sHsp and their targets. Thus, disordered N- and C-terminal sequences play important role in the structure, regulation and functioning of sHsp.

Rescuing Trafficking Mutants of the ATP-binding Cassette Protein, ABCA4, with Small Molecule Correctors as a Treatment for Stargardt Eye Disease

“…HSP 27 can distinguish between different folded states of proteins and prefers binding to conformations that are ultimately folded, rather than binding to totally denatured or wt proteins (13). Hsp 27 can form large oligomers that function as chaperones to prevent the aggregation of misfolded proteins (34). It can be phosphorylated at three serine residues, which can limit the degree of oligomerization and chaperone activity.…”

The functional roles of the unstructured N- and C-terminal regions in αB-crystallin and other mammalian small heat-shock proteins

“…In this paper, we address this question in a general context in terms of the role of unstructured regions in proteins and specifically in relation to flanking regions in sHsps. The role of these regions has been discussed previously in a review of existing structural data (Sudnitsyna et al 2012).…”

Chaperone function and mechanism of small heat-shock proteins

“…In this review, I will focus on how an sHSP activates its numerous multi-type substrate-binding residues and what functional proteins it protects in cells. For readers who are interested in sHSPs with respect to their 3D structures and oligomeric assembly and relevance to human health and physiology, nice review articles are also available [40,[59][60][61][62][63][64].…”