Document Detail


DCNL1 functions as a substrate sensor and activator of cullin 2-RING ligase.
MedLine Citation:
PMID:  23401859     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Substrate engagement by F-box proteins promotes NEDD8 modification of cullins, which is necessary for the activation of cullin-RING E3 ubiquitin ligases (CRLs). However, the mechanism by which substrate recruitment triggers cullin neddylation remains unclear. Here, we identify DCNL1 (defective in cullin neddylation 1-like 1) as a component of CRL2 called ECV (elongins BC/CUL2/VHL) and show that molecular suppression of DCNL1 attenuates CUL2 neddylation. DCNL1 via its DAD patch binds to CUL2 but is also able to bind VHL independent of CUL2 and the DAD patch. The engagement of the substrate hypoxia-inducible factor 1α (HIF1α) to the substrate receptor VHL increases DCNL1 binding to VHL as well as to CUL2. Notably, an engineered mutant form of HIF1α that associates with CUL2, but not DCNL1, fails to trigger CUL2 neddylation and retains ECV in an inactive state. These findings support a model in which substrate engagement prompts DCNL1 recruitment that facilitates the initiation of CUL2 neddylation and define DCNL1 as a "substrate sensor switch" for ECV activation.
Authors:
Pardeep Heir; Roxana I Sufan; Samantha N Greer; Betty P Poon; Jeffrey E Lee; Michael Ohh
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-02-11
Journal Detail:
Title:  Molecular and cellular biology     Volume:  33     ISSN:  1098-5549     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-26     Completed Date:  2013-06-10     Revised Date:  2013-10-08    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1621-31     Citation Subset:  IM    
Affiliation:
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
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MeSH Terms
Descriptor/Qualifier:
Cell Cycle Proteins / genetics,  metabolism*
Cell Line
Cullin Proteins / metabolism*
HEK293 Cells
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis,  genetics,  metabolism*
Mutation
Protein Binding
RNA Interference
RNA, Small Interfering
Ubiquitin-Protein Ligases / metabolism*
Von Hippel-Lindau Tumor Suppressor Protein / metabolism*
Grant Support
ID/Acronym/Agency:
MOP-115066//Canadian Institutes of Health Research; MOP-77718//Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/CUL2 protein, human; 0/Cell Cycle Proteins; 0/Cullin Proteins; 0/DCNL1 protein, human; 0/HIF1A protein, human; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/RNA, Small Interfering; EC 6.3.2.19/Ubiquitin-Protein Ligases; EC 6.3.2.19/VHL protein, human; EC 6.3.2.19/Von Hippel-Lindau Tumor Suppressor Protein
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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