Investigations of the mechanisms of action of human small heat-shock proteins against amyloid fibril formation and pre-formed amyloid fibrils

Abstract

Small heat-shock proteins (sHSPs) are ubiquitously expressed molecular chaperones that protect the proteome against proteostasis failure. sHSPs comprise a conserved alpha-crystallin domain (ACD) flanked by variable N- and C-terminal regions (NTR and CTR, respectively). Heterogenous intermolecular interactions involving the NTR and CTR of sHSPs give rise to polydisperse ensembles of oligomers that readily exchange subunits. This polydispersity renders sHSPs refractory to biophysical characterization by X-ray diffraction and cryogenic electron microscopy, however the ACD can be crystallized. As such, much of the structural information regarding sHSPs has been derived from biophysical studies o..