Proteinaceous Transformers: Structural and Functional Variability of Human sHsps

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 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.

C-Reactive Protein and Cancer: Interpreting the Differential Bioactivities of Its Pentameric and Monomeric, Modified Isoforms

“…Indeed, the role of disulfide bonds as allosteric modulators of protein function is an evolving concept of widespread biochemical relevance ( 60 ) Intramolecular stress contributed by covalently bonded disulfides, which introduce a potential energy of activation in a protein, would be released upon reduction, causing the protein to re-distribute tertiary and quaternary biochemical energies and provide kinetic energy needed to elicit a productive biological response. Protein conformational changes of homo-polymeric proteins (which describes pCRP) can occur when the polymeric protein dissociates, changes conformation, and reassociates into a different quaternary complex (described as “Morpheenins” or “Transformers” ( 61 – 64 ); these changes affect and regulate protein function.…”

Effect of Betaine and Arginine on Interaction of αB-Crystallin with Glycogen Phosphorylase b

“…It is widespread in all tissues, but its concentration is especially high in the eye lens, where it interacts with αA-crystallin (HspB4) and forms a native complex, α-crystallin [ 17 ]. αB-Cr has a dynamic quaternary structure that allows it to form polydisperse assemblies of subunit-exchanging oligomers with chaperone-like activity [ 18 ]. The activity of the chaperone is regulated by a shift in equilibrium between oligomeric forms.…”

“…The activity of the chaperone is regulated by a shift in equilibrium between oligomeric forms. An increase in chaperone activity is associated with the formation of small-sized oligomers (monomer and dimer) [ 18 , 19 , 20 ]. The equilibrium between different oligomeric forms of αB-Cr and chaperone effectiveness is very sensitive to many factors, such as the rate of the target protein aggregation, nature of the aggregation, temperature, the presence of ions, chemical chaperones, etc.…”

Effects of Molecular Crowding and Betaine on HSPB5 Interactions, with Target Proteins Differing in the Quaternary Structure and Aggregation Mechanism

“…sHSPs are ATP-independent chaperones, which bind unfolded protein molecules, thereby preventing their aggregation [ 1 , 2 , 3 , 4 , 5 ]. Under more severe stress conditions, sHSPs even tend to co-precipitate with their non-native substrates in aggregate-like assemblies [ 6 ]. Complexes of sHSPs with target proteins can be further utilized by proteasomal degradation pathways, or unfolded proteins can be refolded by ATP-dependent chaperones [ 6 , 7 ].…”

“…Under more severe stress conditions, sHSPs even tend to co-precipitate with their non-native substrates in aggregate-like assemblies [ 6 ]. Complexes of sHSPs with target proteins can be further utilized by proteasomal degradation pathways, or unfolded proteins can be refolded by ATP-dependent chaperones [ 6 , 7 ]. sHSPs are involved in many important processes in the cell, such as apoptosis, signal transduction, and other vital functions [ 4 , 6 , 7 , 8 , 9 , 10 ].…”