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PMID: 23707686 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Structure of HHARI, a RING-IBR-RING ubiquitin ligase: autoinhibition of an Ariadne-family E3 and insights into ligation mechanism.

Structure (London, England : 1993) ·Vol. 21 ·No. 6 ·2013-06-04 ·Pages 1030-41

Duda DM, Olszewski JL, Schuermann JP, Kurinov I, Miller DJ, Nourse A, Alpi AF, Schulman BA

Abstract

A distinct mechanism for ubiquitin (Ub) ligation has recently been proposed for the RING1-IBR-RING2 (RBR) family of E3s: an N-terminal RING1 domain recruits a thioester-linked intermediate complex between Ub and the E2 UbcH7, and a structurally distinct C-terminal RING2 domain displays a catalytic cysteine required for Ub ligation. To obtain insights into RBR E3s, we determined the crystal structure of the human homolog of Ariadne (HHARI), which reveals the individual RING1, IBR, and RING2 domains embedded in superdomains involving sequences specific to the Ariadne RBR subfamily. The central IBR is flanked on one side by RING1, which is exposed and binds UbcH7. On the other side, a C-terminal autoinhibitory "Ariadne domain" masks the RING2 active site. Insights into RBR E3 mechanisms are provided by structure-based mutations that indicate distinct steps of relief from autoinhibition, Ub transfer from E2 to HHARI, and ligation from the HHARI cysteine to a terminal acceptor.

MeSH Terms
Carrier Proteins/chemistry Humans Models, Molecular Protein Conformation Ubiquitin-Protein Ligases/antagonists & inhibitors,chemistry
Chemicals
Carrier Proteins ARIH1 protein, human Ubiquitin-Protein Ligases
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Duda David M
Howard Hughes Medical Institute, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Olszewski Jennifer L
Schuermann Jonathan P
Kurinov Igor
Miller Darcie J
Nourse Amanda
Alpi Arno F
Schulman Brenda A
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Article Info
Journal
Structure (London, England : 1993)
Abbr.
Structure
ISSN
1878-4186
DOI
10.1016/j.str.2013.04.019
Published
2013-06-04
Epub
2013-00-23
Pages
1030-41
Language
English
Region
United States
NLM ID
101087697
PMCID
PMC3747818
Subset
IM
Grants
NCI NIH HHS · 5P30 CA021765 · United States
NIGMS NIH HHS · P41 GM103403 · United States
NCRR NIH HHS · P41 RR015301 · United States
NIGMS NIH HHS · R01 GM069530 · United States
Howard Hughes Medical Institute · United States
NCI NIH HHS · P30 CA021765 · United States
NIGMS NIH HHS · 8P41 GM103403-10 · United States
NCRR NIH HHS · 5P41 RR015301-10 · United States
Corrections
CommentIn
PMID: 23747110
External Links
PubMed source DOI: 10.1016/j.str.2013.04.019 PMC Full Text View journal details
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