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

Autor: Ayala Mariscal SM; Leibniz Research Institute for Molecular Pharmacology (FMP) im Forschungsverbund Berlin e.V. (FMP), Berlin, Germany., Pigazzini ML; Leibniz Research Institute for Molecular Pharmacology (FMP) im Forschungsverbund Berlin e.V. (FMP), Berlin, Germany.; NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, Berlin, Germany., Richter Y; Department of Cell Biology, University of Bremen, Bremen, Germany., Özel M; Department of Cell Biology, University of Bremen, Bremen, Germany., Grothaus IL; Hybrid Materials Interfaces Group, Faculty of Production Engineering and Bremen Center for Computational Materials Science, University of Bremen, Bremen, Germany.; Center for Environmental Research and Sustainable Technology (UFT), University of Bremen, Bremen, Germany., Protze J; Leibniz Research Institute for Molecular Pharmacology (FMP) im Forschungsverbund Berlin e.V. (FMP), Berlin, Germany., Ziege K; Leibniz Research Institute for Molecular Pharmacology (FMP) im Forschungsverbund Berlin e.V. (FMP), Berlin, Germany., Kulke M; MSU-DOE-Plant Research Laboratory, Michigan State University, 612 Wilson Road, East Lansing, MI, 48824, USA., ElBediwi M; Department of Cell Biology, University of Bremen, Bremen, Germany., Vermaas JV; MSU-DOE-Plant Research Laboratory, Michigan State University, 612 Wilson Road, East Lansing, MI, 48824, USA., Colombi Ciacchi L; Hybrid Materials Interfaces Group, Faculty of Production Engineering and Bremen Center for Computational Materials Science, University of Bremen, Bremen, Germany.; Center for Environmental Research and Sustainable Technology (UFT), University of Bremen, Bremen, Germany.; MAPEX Bremen Center for Materials and Processes, University of Bremen, Bremen, Germany., Köppen S; Hybrid Materials Interfaces Group, Faculty of Production Engineering and Bremen Center for Computational Materials Science, University of Bremen, Bremen, Germany.; MAPEX Bremen Center for Materials and Processes, University of Bremen, Bremen, Germany., Liu F; Leibniz Research Institute for Molecular Pharmacology (FMP) im Forschungsverbund Berlin e.V. (FMP), Berlin, Germany., Kirstein J; Leibniz Research Institute for Molecular Pharmacology (FMP) im Forschungsverbund Berlin e.V. (FMP), Berlin, Germany. kirstein@uni-bremen.de.; Department of Cell Biology, University of Bremen, Bremen, Germany. kirstein@uni-bremen.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Aug 10; Vol. 13 (1), pp. 4692. Date of Electronic Publication: 2022 Aug 10.
DOI: 10.1038/s41467-022-32370-5
Abstrakt: 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 HTTExon1Q 48 . DNAJB1 is the rate-limiting chaperone and we have here identified and characterized the binding interface between DNAJB1 and HTTExon1Q 48 . 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 H244 of the HBM of DNAJB1 completely abrogates the suppression and disaggregation of HTT fibrils by the trimeric chaperone complex. Notably, this mutation does not affect the binding and remodeling of any other protein substrate, suggesting that the HBM of DNAJB1 is a specific interaction site for HTT. Overexpression of wt DNAJB1, but not of DNAJB1 H244A can prevent the accumulation of HTTExon1Q 97 aggregates in HEK293 cells, thus validating the biological significance of the HBM within DNAJB1.
(© 2022. The Author(s).)
Databáze: MEDLINE
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