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Structure of the HECT C‐lobe of the UBR5 E3 ubiquitin ligase

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Abstract:

UBR5 ubiquitin ligase (also known as EDD, Rat100 or hHYD) is a member of the E3 protein family of HECT (homologous to E6‐AP C‐terminus) ligases as it contains a C‐terminal HECT domain. In ubiquitination cascades involving E3s of the HECT class, ubiquitin is transferred from an associated E2 ubiquitin‐conjugating enzyme to the acceptor cysteine of the HECT domain, which consists of structurally distinct N‐ and C‐lobes connected by a flexible linker. Here, the high‐resolution crystal structure of the C‐lobe of the HECT domain of human UBR5 is presented. The structure reveals important features that are unique compared with other HECT domains. In particular, a distinct four‐residue insert in the second helix elongates this helix, resulting in a strikingly different orientation of the preceding loop. This protruding loop is likely to contribute to specificity towards the E2 ubiquitin‐conjugating enzyme UBCH4, which is an important functional partner of UBR5. Ubiquitination assays showed that the C‐lobe of UBR5 is able to form a thioester‐linked E3–ubiquitin complex, although it does not physically interact with UBCH4 in NMR experiments. This study contributes to a better understanding of UBR5 ubiquitination activity.

Document Type: Research Article

DOI: http://dx.doi.org/10.1107/S1744309112036937

Affiliations: Groupe de Recherche axé sur la Structure des Protéines, Department of Biochemistry, McGill University, Montreal, Quebec H3G 0B1, Canada

Publication date: October 1, 2012

bpl/ayf2/2012/00000068/00000010/art00004
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