Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks

Melanie Meister-Broekema, Rebecca Freilich, Chandhuru Jagadeesan, Jennifer N. Rauch, Rocio Bengoechea, William W. Motley, E. F. Elsiena Kuiper, Melania Minoia, Gabriel V. Furtado, Maria A. W. H. Waarde, Shawn J. Bird, Adriana Rebelo, Stephan Zuchner, Peter Pytel, Steven S. Scherer, Federica F. Morelli, Serena Carra, Conrad C. Weihl (), Steven Bergink (), Jason E. Gestwicki () and Harm H. Kampinga ()
Additional contact information
Melanie Meister-Broekema: University Medical Center Groningen, University of Groningen, Department of Biomedical Sciences of Cell & Systems
Rebecca Freilich: Institute for Neurodegenerative Disease, University of California at San Francisco
Chandhuru Jagadeesan: University Medical Center Groningen, University of Groningen, Department of Biomedical Sciences of Cell & Systems
Jennifer N. Rauch: Institute for Neurodegenerative Disease, University of California at San Francisco
Rocio Bengoechea: Washington University School of Medicine
William W. Motley: Johns Hopkins School of Medicine
E. F. Elsiena Kuiper: University Medical Center Groningen, University of Groningen, Department of Biomedical Sciences of Cell & Systems
Melania Minoia: University Medical Center Groningen, University of Groningen, Department of Biomedical Sciences of Cell & Systems
Gabriel V. Furtado: University Medical Center Groningen, University of Groningen, Department of Biomedical Sciences of Cell & Systems
Maria A. W. H. Waarde: University Medical Center Groningen, University of Groningen, Department of Biomedical Sciences of Cell & Systems
Shawn J. Bird: University of Pennsylvania
Adriana Rebelo: University of Miami
Stephan Zuchner: University of Miami
Peter Pytel: University of Chicago Pritzker School of Medicine
Steven S. Scherer: University of Pennsylvania
Federica F. Morelli: University of Modena and Reggio Emilia Modena
Serena Carra: University Medical Center Groningen, University of Groningen, Department of Biomedical Sciences of Cell & Systems
Conrad C. Weihl: Washington University School of Medicine
Steven Bergink: University Medical Center Groningen, University of Groningen, Department of Biomedical Sciences of Cell & Systems
Jason E. Gestwicki: Institute for Neurodegenerative Disease, University of California at San Francisco
Harm H. Kampinga: University Medical Center Groningen, University of Groningen, Department of Biomedical Sciences of Cell & Systems

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract BAG3 is a multi-domain hub that connects two classes of chaperones, small heat shock proteins (sHSPs) via two isoleucine-proline-valine (IPV) motifs and Hsp70 via a BAG domain. Mutations in either the IPV or BAG domain of BAG3 cause a dominant form of myopathy, characterized by protein aggregation in both skeletal and cardiac muscle tissues. Surprisingly, for both disease mutants, impaired chaperone binding is not sufficient to explain disease phenotypes. Recombinant mutants are correctly folded, show unaffected Hsp70 binding but are impaired in stimulating Hsp70-dependent client processing. As a consequence, the mutant BAG3 proteins become the node for a dominant gain of function causing aggregation of itself, Hsp70, Hsp70 clients and tiered interactors within the BAG3 interactome. Importantly, genetic and pharmaceutical interference with Hsp70 binding completely reverses stress-induced protein aggregation for both BAG3 mutations. Thus, the gain of function effects of BAG3 mutants act as Achilles heel of the HSP70 machinery.

Date: 2018
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41467-018-07718-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07718-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-018-07718-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().