The Chaperone Activity of the Developmental Small Heat Shock Protein Sip1 Is Regulated by pH-Dependent Conformational Changes

Small heat shock proteins (sHsps) are ubiquitous molecular chaperones that prevent the aggregation of unfolding proteins during proteotoxic stress. In Caenorhabditis elegans, Sip1 is the only sHsp exclusively expressed in oocytes and embryos. Here, we demonstrate that Sip1 is essential for heat shock survival of reproducing adults and embryos. X-ray crystallography and electron microscopy revealed that Sip1 exists in a range of well-defined globular assemblies consisting of two half-spheres, each made of dimeric “spokes.” Strikingly, the oligomeric distribution of Sip1 as well as its chaperone activity depend on pH, with a trend toward smaller species and higher activity at acidic conditions such as present in nematode eggs. The analysis of the interactome shows that Sip1 has a specific substrate spectrum including proteins that are essential for embryo development. [Display omitted] •Sip1 is a pH-regulated, development-specific molecular chaperone•The crystal structure of the Sip1 32-mer reveals a “mammalian-type” sHsp structure•Cryo-EM 3D reconstructions depict pH-dependent structural plasticity•The interactome shows general protein protection and egg-specific functions Fleckenstein et al. report that the small heat shock protein Sip1 plays an important role as a molecular chaperone during C. elegans development. It is activated at acidic pH in eggs and embryos, and this correlates with changes in its oligomer structure.