@article{0d74efafe2714b1b9d8657835d512089,
title = "A Tunable Brake for HECT Ubiquitin Ligases",
abstract = "The HECT E3 ligases ubiquitinate numerous transcription factors and signaling molecules, and their activity must be tightly controlled to prevent cancer, immune disorders, and other diseases. In this study, we have found unexpectedly that peptide linkers tethering WW domains in several HECT family members are key regulatory elements of their catalytic activities. Biochemical, structural, and cellular analyses have revealed that the linkers can lock the HECT domain in an inactive conformation and block the proposed allosteric ubiquitin binding site. Such linker-mediated autoinhibition of the HECT domain can be relieved by linker post-translational modifications, but complete removal of the brake can induce hyperactive autoubiquitination and E3 self destruction. These results clarify the mechanisms of several HECT protein cancer associated mutations and provide a new framework for understanding how HECT ubiquitin ligases must be finely tuned to ensure normal cellular behavior.",
author = "Zan Chen and Hanjie Jiang and Wei Xu and Xiaoguang Li and Dempsey, {Daniel R.} and Xiangbin Zhang and Peter Devreotes and Cynthia Wolberger and Amzel, {L. Mario} and Gabelli, {Sandra B.} and Cole, {Philip A.}",
note = "Funding Information: We thank the NIH (CA74305, CAGM62437, CA043460), DOD (CDMRP BC151831), and FAMRI Foundation for support. We thank Drs. Wenyi Wei, Allan Weissman, and Xuejun Xiang for DNA plasmids. We are grateful to Yana Li for assistance with cell culture. We acknowledge the use of the Berkeley Center for Structural Biology, which is supported in part by NIGMS and HHMI. The Advanced Light Source is supported by the U.S. Department of Energy (D.O.E.) under contract no. DE-AC02-05CH11231. This research used resources of the Advanced Photon Source (a U.S. D.O.E.) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. Use of the Lilly Research Laboratories Collaborative Access Team (LRL-CAT) beam line at Sector 31 of the Advanced Photon Source was provided by Eli Lilly Company, which operates the facility.",
year = "2017",
month = may,
day = "4",
doi = "10.1016/j.molcel.2017.03.020",
language = "English (US)",
volume = "66",
pages = "345--357.e6",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "3",
}