例如:"lncRNA", "apoptosis", "WRKY"

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

Nat Commun. 2018 Dec 17;9(1):5342
Melanie Meister-Broekema 1 , Rebecca Freilich 2 , Chandhuru Jagadeesan 3 , Jennifer N Rauch 2 , Rocio Bengoechea 4 , William W Motley 5 , E F Elsiena Kuiper 1 , Melania Minoia 1 , Gabriel V Furtado 6 , Maria A W H van Waarde 1 , Shawn J Bird 7 , Adriana Rebelo 8 , Stephan Zuchner 8 , Peter Pytel 9 , Steven S Scherer 7 , Federica F Morelli 10 , Serena Carra 10 , Conrad C Weihl 11 , Steven Bergink 12 , Jason E Gestwicki 13 , Harm H Kampinga 14
Melanie Meister-Broekema 1 , Rebecca Freilich 2 , Chandhuru Jagadeesan 3 , Jennifer N Rauch 2 , Rocio Bengoechea 4 , William W Motley 5 , E F Elsiena Kuiper 1 , Melania Minoia 1 , Gabriel V Furtado 6 , Maria A W H van Waarde 1 , Shawn J Bird 7 , Adriana Rebelo 8 , Stephan Zuchner 8 , Peter Pytel 9 , Steven S Scherer 7 , Federica F Morelli 10 , Serena Carra 10 , Conrad C Weihl 11 , Steven Bergink 12 , Jason E Gestwicki 13 , Harm H Kampinga 14
+ et al

[No authors listed]

Author information
  • 1 University Medical Center Groningen, University of Groningen, Department of Biomedical Sciences of Cell & Systems, Groningen, AV, 9791, The Netherlands.
  • 2 Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, CA, 94158, USA.
  • 3 Max Planck Institute of Biochemistry, Martinsried/Munich, 82152, Germany.
  • 4 Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
  • 5 Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
  • 6 Programa de Pós-Graduação em Genética e Biologia Molecular, Department of Genetics, Universidade Federal do Rio Grande do SulPorto Alegre, Porto Alegre, 15053, Brazil.
  • 7 Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 8 Department of Human Genetics and Hussman Institute for Human Genomics, University of Miami, Miami, FL, 33136, USA.
  • 9 Department of Neuropathology, University of Chicago Pritzker School of Medicine, Chicago, IL, 60637, USA.
  • 10 Department of Biomedical, Metabolic and Neural Sciences, Center for Neuroscience and Nanotechnology, University of Modena and Reggio Emilia Modena, Modena, 41125, Italy.
  • 11 Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA. weihlc@wustl.edu.
  • 12 University Medical Center Groningen, University of Groningen, Department of Biomedical Sciences of Cell & Systems, Groningen, AV, 9791, The Netherlands. s.bergink@umcg.nl.
  • 13 Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, CA, 94158, USA. Jason.Gestwicki@ucsf.edu.
  • 14 University Medical Center Groningen, University of Groningen, Department of Biomedical Sciences of Cell & Systems, Groningen, AV, 9791, The Netherlands. h.h.kampinga@umcg.nl.

摘要


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.