Identification of a HTT-specific binding motif in DNAJB1 essential for suppression and disaggregation of HTT.

ABSTRACT: Huntington's disease is a neurodegenerative disease caused by an expanded polyQ stretch within Huntingtin (HTT) that renders the protein aggregation-prone, ultimately resulting in the formation of amyloid fibrils. A trimeric chaperone complex composed of Hsc70, DNAJB1 and Apg2 can suppress and reverse the aggregation of HTTExon1Q₄₈. DNAJB1 is the rate-limiting chaperone and we have here identified and characterized the binding interface between DNAJB1 and HTTExon1Q₄₈. DNAJB1 exhibits a HTT binding motif (HBM) in the hinge region between C-terminal domains (CTD) I and II and binds to the polyQ-adjacent proline rich domain (PRD) of soluble as well as aggregated HTT. The PRD of HTT represents an additional binding site for chaperones. Mutation of the highly conserved H24

SUBMITTER: Ayala Mariscal SM 

PROVIDER: S-EPMC9365803 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature