All organisms rely on a conserved cellular machinery supporting and controlling the life cycle of proteins: the proteostasis network. Within this network, the main players that determine the fate of proteins are molecular chaperones, the ubiquitin-proteasome and the lysosome-autophagy systems. sHsps (small heat-shock proteins) represent one family of molecular chaperones found in all domains of life. They prevent irreversible aggregation of unfolded proteins and maintain proteostasis by stabilizing promiscuously a variety of non-native proteins in an ATP-independent manner. In the cellular chaperone network, sHsps act as the first line of defence and keep their substrates in a folding-competent state until they are refolded by downstream ATP-dependent chaperone systems. Besides this interaction with unfolding substrates upon stress, sHsps show a different mode of binding for specific clients which are also recognized under physiological conditions. In vertebrates, sHsps are especially needed to maintain the refractive index of the eye lens. Additionally, sHsps are linked to a broad variety of diseases such as myopathies and neuropathies. The most striking feature of sHsps is their ability to form dynamic ensembles of higher oligomers. The activity of sHsps is regulated by changes in the composition of the ensembles.
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.
The Fourth Cell Stress Society International workshop on small heat shock proteins (sHSPs), a follow-up to successful workshops held in 2014, 2016 and 2018, took place as a virtual meeting on the 17-18 November 2022. The meeting was designed to provide an opportunity for those working on sHSPs to reconnect and discuss their latest work. The diversity of research in the sHSP field is reflected in the breadth of topics covered in the talks presented at this meeting. Here we summarise the presentations at this meeting and provide some perspectives on exciting future topics to be addressed in the field.
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