The Big Book on Small Heat Shock Proteins

Abstract

Heat Shock Proteins: key mediators of Health and Disease. Heat shock proteins (HSP) are essential molecules conserved through cellular evolution required for cells to survive the stresses encountered in the environment and in the tissues of the developing and aging organism. These proteins play the essential roles in stress of preventing the initiation of programmed cell death and repairing damage to the proteome permitting resumption of normal metabolism. Loss of the HSP is lethal either in the short-term in cases of acute stress or in the long-term when exposure to stress is chronic. Cells appear to walk a fi ne line in terms of HSP expression. If expression falls below a certain level, cells become sensitive to oxidative damage that infl uences aging and protein aggregation disease. If HSP levels rise above the normal range, infl ammatory and oncogenic changes occur. It is becoming clear that HSP are emerging as remarkably versatile mediators of health and disease. The aim of this series of volumes is to examine how HSP regulation and expression become altered in pathological states and how this may be remedied by pharmacological and other interventions.More information about this series at

It takes a dimer to tango: Oligomeric small heat shock proteins dissociate to capture substrate

“…Small heat-shock proteins (sHsps) 5 are a class of ATP-independent chaperones, expressed across all kingdoms of life, that are proposed to act as a cell's "first-responders" under stress conditions (1)(2)(3)(4)(5)(6). Mutations or misexpression of specific human sHsps are associated with myopathies, neuropathies, and cancers (1,(7)(8)(9).…”

“…sHsps are characterized by a 90 -amino acid, ␤-sheet-rich ␣-crystallin domain (ACD, or Hsp20 domain, PF00011), flanked by sequences of variable length and composition (N-terminal (NT) sequence; C-terminal (CT) sequence) (11,12). The majority form large oligomers containing 12 to Ͼ40 units, with a dimeric substructure (1,3,5), although there are a few dimeric sHsps, some of which are active chaperones (5,(13)(14)(15). Although vertebrate sHsps assemble principally as polydisperse oligomers, some bacterial, yeast, and plant sHsps are monodisperse.…”

“…Although vertebrate sHsps assemble principally as polydisperse oligomers, some bacterial, yeast, and plant sHsps are monodisperse. In all oligomeric forms, sHsp dimers interact through a conserved interface between an I-X-I motif in the CT and a groove formed by ␤4 and ␤8 in the ACD of a monomer in another dimer (hereafter the CT-ACD interface) (1,5,16,17). Notably, sHsp oligomers are also highly dynamic, exchanging dimers (and monomers) on a timescale of minutes, as fast or faster than their rate of substrate capture.…”

“…The large size, dynamic nature, and inherent polydispersity of most sHsps have resulted in few high-resolution structures (17-22) and differing hypotheses on sHsp mode of action. Interaction with substrates has been proposed to require either conformational changes in the oligomer or dissociation of oligomers into active units (3)(4)(5). A mechanism involving structural rearrangements of the oligomers is supported by presence of multiple oligomer conformations (23)(24)(25), with a shift in equilibria proposed to activate the sHsp.…”

Dysregulated interactions triggered by a neuropathy-causing mutation in the IPV motif of HSP27

“…Our results provide a mechanistic basis for the impact of the P182L mutation on HSP27, and highlight the general importance of the IxI/V motif and its role in protein-protein interaction networks. Introduction HSP27 (HSPB1) is a systemically expressed human small heat-shock protein (sHSP) that performs diverse functions under basal and stressful cellular conditions (1)(2)(3). With significant roles in the maintenance of protein homeostasis, regulation of the redox environment, prevention of apoptosis, and stabilization of the cytoskeletal network, the biological activity of HSP27 is critical to overall cellular health (4)(5)(6)(7)(8).…”