Abstract
Hsp26 is a small heat shock protein (sHsp) from S. cerevisiae. Its chaperone activity is activated by oligomer dissociation at heat shock temperatures. Hsp26 contains 9 phosphorylation sites in different structural elements. Our analysis of phospho-mimetic mutations shows that phosphorylation activates Hsp26 at permissive temperatures. The cryo-EM structure of the Hsp26 40mer revealed contacts between the conserved core domain of Hsp26 and the so-called thermosensor domain in the N-terminal part of the protein, which are targeted by phosphorylation. Furthermore, several phosphorylation sites in the C-terminal extension, which link subunits within the oligomer, are sensitive to the introduction of negative charges. In all cases, the intrinsic inhibition of chaperone activity is relieved and the N-terminal domain becomes accessible for substrate protein binding. The weakening of domain interactions within and between subunits by phosphorylation to activate the chaperone activity in response to proteotoxic stresses independent of heat stress could be a general regulation principle of sHsps.
Highlights
heat shock proteins (Hsps)[26] is a small heat shock protein from S. cerevisiae
The central conserved domain of small heat shock protein (sHsp) is termed α-crystallin domain (ACD). This domain is flanked by an N-terminal region (NTR), which is of variable length and sequence, and a short C-terminal region (CTR)24,25. sHsps form large polydisperse oligomers consisting of dimeric building blocks[5,26,27,28]
We set out to understand the effects of phosphorylation on the structure and the activity of Hsp[26] from S. cerevisiae
Summary
Phosphorylation-mimetic Hsp[26] mutants are more active at strate complexes. To gain further insight into the nature of the lower temperatures. Phospho-proteomic studies had revealed chaperoning mechanism of the phosphorylation-mimetic
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