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Review
. 2020 Jul;25(4):601-613.
doi: 10.1007/s12192-020-01095-z. Epub 2020 Apr 6.

Small heat-shock proteins and their role in mechanical stress

Miranda P Collier  1 , Justin L P Benesch  2
Affiliations
Review

Small heat-shock proteins and their role in mechanical stress

Miranda P Collier et al. Cell Stress Chaperones. 2020 Jul.

Abstract

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 interactions - enabled by the development of experimental methodologies that allow protein contacts to be studied under the application of mechanical force - will expand our understanding of the activity and functions of sHSPs, and of the roles played by chaperones in general.

Keywords: Cardiomyocytes; FLNC; Filamin C; HspB8; Mechanical stress; Mechanosensing; Molecular chaperones; Monodispersity; Muscle; Polydispersity; Proteostasis; Small heat-shock proteins; sHSPs.

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Figures

Fig. 1
Fig. 1
Chaperones modulate the stability of the proteome toward a variety of stressors. a A protein energy landscape. Unfolded proteins sample conformations to reach a flexible functional or `native’ state. Destabilized proteins can attract intermolecular interactors through exposure of hydrophobic regions, prompting a cascade to aggregation which can be either protective (Sontag et al. 2017) or pathological (Hipp et al. 2014). Some oligomeric precursors can also form highly thermodynamically stable fibrillar aggregates, which are associated with diseases (Chiti and Dobson 2006). Chaperones affect various pathways along this energy landscape. b. The most prominent roles of mammalian heat-shock proteins during cellular response to stress, as part of the maintenance stage of the protein `life cycle’. An environmental, biochemical, or mechanical change causes native protein to misfold. It is then either bound by ATP-dependent HSP machinery (HSP40, HSP70, and HSP90) for refolding or sequestered by sHSPs to prevent aggregation rapidly with less metabolic cost to the cell. Most sHSPs form large oligomers often disrupted by stress conditions (Haslbeck et al. 2016). Additional chaperone complexes (involving HSP40, HSP70, and HSP110) promote aggregate clearance through disassembly or degradation. HSP60 (not pictured) is a mitochondrial chaperone. Schematics influenced by (Kim et al. ; Carver et al. ; Richter et al. ; Garrido et al. 2012)
Fig. 2
Fig. 2
Structural regions of sHSPs and hierarchy of assembly. a. The primary sequence encodes three domains: a central β-sheet rich ACD flanked by N- and C-terminal regions. Truncating the termini (faded regions) reduces polydispersity and facilitates crystallization. b. X-ray structure of the HspB5 ACD and partial C-terminus, showing 4 monomers (Laganowsky et al. 2010). The ACD dimerizes via an antiparallel (AP) interface between strands β6 + 7. The C-terminus bridges dimers by docking into a groove between strands β4 and β8 via the I-X-I motif (sticks; in HspB5, X = proline). c. The contacts comprising the AP interface may shift under different conditions, evidenced by the observation of three registers of the HspB5 dimer by X-ray crystallography (PDB IDs 3L1G, 2WJ7, 4M5S). Multiple registers of the HspB1 ACD dimer have also been captured in X-ray structures (H. Gastall, unpublished)
Fig. 3
Fig. 3
Phosphorylated HspB1 modulates the extension of FLNC with implications for cardiac function under mechanical stress. a. Western blots of FLNC, HspB1, and GAPDH as loading control from mouse hearts reveal upregulation of both proteins following mechanical stress. WT = wild-type; KO = muscle LIM protein knockout, a transgenic model of biomechanical dysfunction; Sh = sham surgery control; TAC = transverse aortic constriction; S = saline control; IsoPE = isoprenaline/epinephrine treatment. b. Measurement of FLNC domains 18–21 binding to peptides derived from HspB1 residues 80–88, without and with phosphorylation at Ser82. c. Coulombically steered unfolding of FLNC domains 18–21 bound to a single HspB1 peptide, unmodified (top) or phosphorylated (bottom). Lines designate the activation required to transition half of an intermediate FLNC state to a more unfolded state, which is delayed when bound to HspB1 phosphopeptide. d. Schematic of force-induced changes to FLNC captured by coulombic unfolding, in relation to full-length FLNC, HspB1 peptide binding, and HspB8/BAG3 mediated clearance. This figure is derived from Collier et al. (DOI: 10.1126/sciadv.aav8421), licensed under CC BY 4.0
Fig. 4
Fig. 4
Conceptual view of the sHSP functional landscape
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