A Tunable Brake for HECT Ubiquitin Ligases

Zan Chen, Hanjie Jiang, Wei Xu, Xiaoguang Li, Daniel R. Dempsey, Xiangbin Zhang, Peter Devreotes, Cynthia Wolberger, L. Mario Amzel, Sandra B. Gabelli, Philip A. Cole

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)345-357.e6
JournalMolecular Cell
Volume66
Issue number3
DOIs
StatePublished - May 4 2017

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Ligases
Ubiquitin
Neoplasms
Ubiquitin-Protein Ligases
Immune System Diseases
Post Translational Protein Processing
Transcription Factors
Binding Sites
Peptides
Mutation
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Chen, Z., Jiang, H., Xu, W., Li, X., Dempsey, D. R., Zhang, X., ... Cole, P. A. (2017). A Tunable Brake for HECT Ubiquitin Ligases. Molecular Cell, 66(3), 345-357.e6. DOI: 10.1016/j.molcel.2017.03.020

A Tunable Brake for HECT Ubiquitin Ligases. / Chen, Zan; Jiang, Hanjie; Xu, Wei; Li, Xiaoguang; Dempsey, Daniel R.; Zhang, Xiangbin; Devreotes, Peter; Wolberger, Cynthia; Amzel, L. Mario; Gabelli, Sandra B.; Cole, Philip A.

In: Molecular Cell, Vol. 66, No. 3, 04.05.2017, p. 345-357.e6.

Research output: Contribution to journalArticle

Chen, Z, Jiang, H, Xu, W, Li, X, Dempsey, DR, Zhang, X, Devreotes, P, Wolberger, C, Amzel, LM, Gabelli, SB & Cole, PA 2017, 'A Tunable Brake for HECT Ubiquitin Ligases' Molecular Cell, vol 66, no. 3, pp. 345-357.e6. DOI: 10.1016/j.molcel.2017.03.020
Chen Z, Jiang H, Xu W, Li X, Dempsey DR, Zhang X et al. A Tunable Brake for HECT Ubiquitin Ligases. Molecular Cell. 2017 May 4;66(3):345-357.e6. Available from, DOI: 10.1016/j.molcel.2017.03.020

Chen, Zan; Jiang, Hanjie; Xu, Wei; Li, Xiaoguang; Dempsey, Daniel R.; Zhang, Xiangbin; Devreotes, Peter; Wolberger, Cynthia; Amzel, L. Mario; Gabelli, Sandra B.; Cole, Philip A. / A Tunable Brake for HECT Ubiquitin Ligases.

In: Molecular Cell, Vol. 66, No. 3, 04.05.2017, p. 345-357.e6.

Research output: Contribution to journalArticle

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