Article
- The EMBO Journal (2008) 27, 2862 - 2872
- doi:10.1038/emboj.2008.199
Published online: 16 October 2008
Subject Categories:
Regulated association of misfolded endoplasmic reticulum lumenal proteins with P58/DNAJc3
Kseniya Petrova1,2,3, Seiichi Oyadomari1,2,3, Linda M Hendershot4 and David Ron1,2,3
- Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY, USA
- Department of Cell Biology, New York University School of Medicine, New York, NY, USA
- Department of Medicine, New York University School of Medicine, New York, NY, USA
- Department of Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN, USA
Correspondence to:
David Ron, New York University School of Medicine, SI 3-10, 540 First Avenue, New York, NY 10016, USA. Tel.: +1 212 263 7786; Fax: +1 212 263 8951; E-mail: ron@saturn.med.nyu.edu
Received 8 August 2008; Accepted 5 September 2008
Abstract
P58/DNAJc3 defends cells against endoplasmic reticulum (ER) stress. Most P58 molecules are translocated into the ER lumen, and here we report selective and stable binding to misfolded proteins by P58's TPR-containing N-terminal domain. In vitro, too, P58 binds selectively to a model misfolded protein and challenge of that complex with physiological concentrations of the ER lumenal Hsp70-type chaperone BiP encourages disassembly. BiP-induced dissociation of P58 from its substrate depends on the presence of ATP and on interactions with P58's J-domain, which are mediated by invariant residues BiPR197 and P58H422. A functional J-domain also accelerates dissociation of P58 from a model substrate, VSV-Gts045, on the latter's re-folding in vivo. However, J-domain binding can be separated from the ability to promote substrate dissociation by the mutant BiPE201G and a wild-type J-domain fused ectopically to P58H422Q rescues the latter's inability to dissociate from substrate in response to BiP and ATP. These findings are consistent with a model whereby localized activation of the Hsp70-type partner is sufficient to promote substrate handover from the J-domain co-chaperone.
Keywords:
- chaperones,
- endoplasmic reticulum,
- protein folding,
- translation
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