Itch WW Domains Inhibit Its E3 Ubiquitin Ligase Activity by Blocking E2-E3 Ligase Trans-thiolation.

Autor:	Riling C; From the Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104., Kamadurai H; the St. Jude Children's Research Hospital, Memphis, Tennessee 38105., Kumar S; Progenra Inc., Malvern, Pennsylvania 19355., O'Leary CE; From the Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104., Wu KP; the St. Jude Children's Research Hospital, Memphis, Tennessee 38105., Manion EE; Progenra Inc., Malvern, Pennsylvania 19355., Ying M; the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104., Schulman BA; the St. Jude Children's Research Hospital, Memphis, Tennessee 38105, the Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, and., Oliver PM; From the Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, the Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 paulao@mail.med.upenn.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2015 Sep 25; Vol. 290 (39), pp. 23875-87. Date of Electronic Publication: 2015 Aug 05.
DOI:	10.1074/jbc.M115.649269
Abstrakt:	Nedd4-family E3 ubiquitin ligases regulate an array of biologic processes. Autoinhibition maintains these catalytic ligases in an inactive state through several mechanisms. However, although some Nedd4 family members are activated by binding to Nedd4 family-interacting proteins (Ndfips), how binding activates E3 function remains unclear. Our data reveal how these two regulatory processes are linked functionally. In the absence of Ndfip1, the Nedd4 family member Itch can bind an E2 but cannot accept ubiquitin onto its catalytic cysteine. This is because Itch is autoinhibited by an intramolecular interaction between its HECT (homologous to the E6-AP carboxy terminus domain) and two central WW domains. Ndfip1 binds these WW domains to release the HECT, allowing trans-thiolation and Itch catalytic activity. This molecular switch also regulates the closely related family member WWP2. Importantly, multiple PY motifs are required for Ndfip1 to activate Itch, functionally distinguishing Ndfips from single PY-containing substrates. These data establish a novel mechanism for control of the function of a subfamily of Nedd4 E3 ligases at the level of E2-E3 trans-thiolation. (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)
Databáze:	MEDLINE
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