The function of small heat-shock proteins and their implication in proteostasis

Strauch, Annika; Haslbeck, Martin

doi:10.1042/ebc20160010

Cited by 30 publications

(26 citation statements)

References 67 publications

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“…Terminology has been proposed to distinguish between sHSP interactors that are destabilized under stress and those that are bound physiologically by referring to these as substrates and clients, respectively (Strauch and Haslbeck 2016), although the boundaries between the two are not always clear. In muscle for example, which expresses the greatest variety of sHSPs in humans (Table 1), several sHSPs interact with cytoskeletal components and associated proteins (Mounier and Arrigo 2002;Bennardini et al 1992;Houck and Clark 2010;Wu et al 2017;Tessier et al 2003).…”

Section: Functions and Interactorsmentioning

confidence: 99%

Small heat-shock proteins and their role in mechanical stress

Collier

Benesch

2020

Cell Stress and Chaperones

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The ability of cells to respond to stress is central to health. Stress can damage folded proteins, which are vulnerable to even minor changes in cellular conditions. To maintain proteostasis, cells have developed an intricate network in which molecular chaperones are key players. The small heat-shock proteins (sHSPs) are a widespread family of molecular chaperones, and some sHSPs are prominent in muscle, where cells and proteins must withstand high levels of applied force. sHSPs have long been thought to act as general interceptors of protein aggregation. However, evidence is accumulating that points to a more specific role for sHSPs in protecting proteins from mechanical stress. Here, we briefly introduce the sHSPs and outline the evidence for their role in responses to mechanical stress. We suggest that sHSPs interact with mechanosensitive proteins to regulate physiological extension and contraction cycles. It is likely that further study of these interactionsenabled by the development of experimental methodologies that allow protein contacts to be studied under the application of mechanical forcewill expand our understanding of the activity and functions of sHSPs, and of the roles played by chaperones in general.

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Section: Functions and Interactorsmentioning

confidence: 99%

Small heat-shock proteins and their role in mechanical stress

Collier

Benesch

2020

Cell Stress and Chaperones

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“…Small Hsps exhibit chaperone-like activity in preventing aggregation of target proteins, maintaining them in a folding–competent state and refolding them independently or in concert with other ATP-dependent chaperones such as Hsp70s (McGreal et al, 2012). For a more comprehensive review on small Hsps, the authors suggest Strauch and Haslbeck (2016). …”

Section: Protein Folding and Chaperonesmentioning

confidence: 99%

The Role of Co-chaperones in Synaptic Proteostasis and Neurodegenerative Disease

2017

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Synapses must be preserved throughout an organism's lifespan to allow for normal brain function and behavior. Synapse maintenance is challenging given the long distances between the termini and the cell body, reliance on axonal transport for delivery of newly synthesized presynaptic proteins, and high rates of synaptic vesicle exo- and endocytosis. Hence, synapses rely on efficient proteostasis mechanisms to preserve their structure and function. To this end, the synaptic compartment has specific chaperones to support its functions. Without proper synaptic chaperone activity, local proteostasis imbalances lead to neurotransmission deficits, dismantling of synapses, and neurodegeneration. In this review, we address the roles of four synaptic chaperones in the maintenance of the nerve terminal, as well as their genetic links to neurodegenerative disease. Three of these are Hsp40 co-chaperones (DNAJs): Cysteine String Protein alpha (CSPα; DNAJC5), auxilin (DNAJC6), and Receptor-Mediated Endocytosis 8 (RME-8; DNAJC13). These co-chaperones contain a conserved J domain through which they form a complex with heat shock cognate 70 (Hsc70), enhancing the chaperone's ATPase activity. CSPα is a synaptic vesicle protein known to chaperone the t-SNARE SNAP-25 and the endocytic GTPase dynamin-1, thereby regulating synaptic vesicle exocytosis and endocytosis. Auxilin binds assembled clathrin cages, and through its interactions with Hsc70 leads to the uncoating of clathrin-coated vesicles, a process necessary for the regeneration of synaptic vesicles. RME-8 is a co-chaperone on endosomes and may have a role in clathrin-coated vesicle endocytosis on this organelle. These three co-chaperones maintain client function by preserving folding and assembly to prevent client aggregation, but they do not break down aggregates that have already formed. The fourth synaptic chaperone we will discuss is Heat shock protein 110 (Hsp110), which interacts with Hsc70, DNAJAs, and DNAJBs to constitute a disaggregase. Hsp110-related disaggregase activity is present at the synapse and is known to protect against aggregation of proteins such as α-synuclein. Congruent with their importance in the nervous system, mutations of these co-chaperones lead to familial neurodegenerative disease. CSPα mutations cause adult neuronal ceroid lipofuscinosis, while auxilin mutations result in early-onset Parkinson's disease, demonstrating their significance in preservation of the nervous system.

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“…Humans express 10 distinct sHSP that have critical physiological roles including maintenance of lens transparency and the integrity of cardiac and skeletal muscles [7][8][9][10][11] . Mutations in human sHSP have been associated with inherited diseases, most notably cataract and cardiomyopathy [12][13][14][15][16][17] .…”

Section: Introductionmentioning

confidence: 99%

Engineering of a Polydisperse Small Heat-Shock Protein Reveals Conserved Motifs of Oligomer Plasticity

Mishra

Chandler

Williams

et al. 2018

Preprint

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Small heat-shock proteins (sHSP) are molecular chaperones that bind and sequester partially and globally unfolded states of their client proteins. Of paramount importance to their physiological roles is the assembly into large oligomers, which for mammalian sHSP are polydisperse and undergo subunit exchange. The flexibility and dynamic nature of these oligomers mediates functional regulation by phosphorylation and underpins the deleterious effects of disease-linked mutations. Previously, we discovered that the archaeal Hsp16.5, which natively forms ordered and symmetric 24-subunit oligomers, can be engineered to transition to an ordered and symmetric 48-subunit oligomer by insertion of a peptide from human HspB1 (Hsp27) at the junction of the N-terminal and α-crystallin domains. Here, we carried out a detailed analysis of the determinants of Hsp16.5 oligomeric plasticity by altering the sequence and length of the inserted peptide. Utilizing light scattering, blue native gel electrophoresis, native mass spectrometry and electron microscopy, we uncovered the existence of an array of oligomeric states (30 to 38 subunits) that can be populated as a consequence of different insertions. These oligomers are intermediate states on the assembly pathway of the 48-subunit oligomer as two of the variants can concurrently form 24-subunit or 30-38 subunit polydisperse oligomers. Polydisperse Hsp16.5 oligomers displayed higher affinity to a model client protein consistent with a general mechanism for recognition and binding that involves increased access of the hydrophobic N-terminal region. Our findings, which integrate structural and functional analyses from evolutionarily-distant sHSP, support a model wherein the modular architecture of these proteins encodes motifs of oligomer polydispersity, dissociation and expansion to achieve functional diversity and regulation.peer-reviewed)

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The function of small heat-shock proteins and their implication in proteostasis

Cited by 30 publications

References 67 publications

Small heat-shock proteins and their role in mechanical stress

Small heat-shock proteins and their role in mechanical stress

The Role of Co-chaperones in Synaptic Proteostasis and Neurodegenerative Disease

Engineering of a Polydisperse Small Heat-Shock Protein Reveals Conserved Motifs of Oligomer Plasticity

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