NDLI: Mechanism of ubiquitin chain synthesis employed by a HECT domain ubiquitin ligase

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Mechanism of ubiquitin chain synthesis employed by a HECT domain ubiquitin ligase

Content Provider	Scilit
Author	French, Michael E. Klosowiak, Julian L. Aslanian, Aaron Reed, Steven I. Yates, John R. Hunter, Tony
Copyright Year	2017
Description	Journal: Journal of Biological Chemistry Homologous to E6AP C-terminal (HECT) ubiquitin (Ub) ligases (E3s) are a large class of enzymes that bind to their substrates and catalyze ubiquitination through the formation of a Ub thioester intermediate. The mechanisms by which these E3s assemble polyubiquitin chains on their substrates remain poorly defined. We report here that the Nedd4 family HECT E3, WWP1, assembles substrate-linked Ub chains containing Lys-63, Lys-48, and Lys-11 linkages (Lys-63 > Lys-48 > Lys-11). Our results demonstrate that WWP1 catalyzes the formation of Ub chains through a sequential addition mechanism, in which Ub monomers are transferred in a successive fashion to the substrate, and that ubiquitination by WWP1 requires the presence of a low-affinity, noncovalent Ub-binding site within the HECT domain. Unexpectedly, we find that the formation of Ub chains by WWP1 occurs in two distinct phases. In the first phase, chains are synthesized in a unidirectional manner and are linked exclusively through Lys-63 of Ub. In the second phase, chains are elongated in a multidirectional fashion characterized by the formation of mixed Ub linkages and branched structures. Our results provide new insight into the mechanism of Ub chain formation employed by Nedd4 family HECT E3s and suggest a framework for understanding how this family of E3s generates Ub signals that function in proteasome-independent and proteasome-dependent pathways.
Related Links	http://www.jbc.org/content/292/25/10398.full.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481553/pdf http://www.jbc.org/article/S0021925820395855/pdf
Ending Page	10413
Page Count	16
Starting Page	10398
ISSN	00219258
e-ISSN	1083351X
DOI	10.1074/jbc.m117.789479
Journal	Journal of Biological Chemistry
Issue Number	25
Volume Number	292
Language	English
Publisher	Elsevier BV
Publisher Date	2017-06-01
Access Restriction	Open
Subject Keyword	Journal: Journal of Biological Chemistry Biochemistry and Molecular Biology E3 Ubiquitin Ligase Polyubiquitin Chain Protein Degradation Ubiquitylation (ubiquitination)
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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