Disease-associated mutations within the yeast DNAJB6 homolog Sis1 slow conformer-specific substrate processing and can be corrected by the modulation of nucleotide exchange factors

Ankan K. Bhadra, Michael J. Rau, Jil A. Daw, James A. J. Fitzpatrick, Conrad C. Weihl and Heather L. True ()
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Ankan K. Bhadra: Washington University School of Medicine
Michael J. Rau: Washington University Center for Cellular Imaging (WUCCI), Washington University School of Medicine
Jil A. Daw: Washington University School of Medicine
James A. J. Fitzpatrick: Washington University School of Medicine
Conrad C. Weihl: Washington University School of Medicine
Heather L. True: Washington University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Molecular chaperones, or heat shock proteins (HSPs), protect against the toxic misfolding and aggregation of proteins. As such, mutations or deficiencies within the chaperone network can lead to disease. Dominant mutations within DNAJB6 (Hsp40)—an Hsp70 co-chaperone—lead to a protein aggregation-linked myopathy termed Limb-Girdle Muscular Dystrophy Type D1 (LGMDD1). Here, we used the yeast prion model client in conjunction with in vitro chaperone activity assays to gain mechanistic insights into the molecular basis of LGMDD1. Here, we show how mutations analogous to those found in LGMDD1 affect Sis1 (a functional homolog of human DNAJB6) function by altering the structure of client protein aggregates, interfering with the Hsp70 ATPase cycle, dimerization and substrate processing; poisoning the function of wild-type protein. These results uncover the mechanisms through which LGMDD1-associated mutations alter chaperone activity, and provide insights relevant to potential therapeutic interventions.

Date: 2022
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DOI: 10.1038/s41467-022-32318-9

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