A multi-lock inhibitory mechanism for fine-tuning enzyme activities of the HECT family E3 ligases

Zhen Wang, Ziheng Liu, Xing Chen, Jingyu Li, Weiyi Yao, Shijing Huang, Aihong Gu, Qun-Ying Lei, Ying Mao and Wenyu Wen ()
Additional contact information
Zhen Wang: Fudan University
Ziheng Liu: Fudan University
Xing Chen: Fudan University
Jingyu Li: Fudan University
Weiyi Yao: Fudan University
Shijing Huang: Fudan University
Aihong Gu: Fudan University
Qun-Ying Lei: Fudan University
Ying Mao: Fudan University
Wenyu Wen: Fudan University

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract HECT E3 ligases control the degradation and functioning of numerous oncogenic/tumor-suppressive factors and signaling proteins, and their activities must be tightly regulated to prevent cancers and other diseases. Here we show that the Nedd4 family HECT E3 WWP1 adopts an autoinhibited state, in which its multiple WW domains sequester HECT using a multi-lock mechanism. Removing WW2 or WW34 led to a partial activation of WWP1. The structure of fully inhibited WWP1 reveals that many WWP1 mutations identified in cancer patients result in a partially active state with increased E3 ligase activity, and the WWP1 mutants likely promote cell migration by enhancement of ∆Np63α degradation. We further demonstrate that WWP2 and Itch utilize a highly similar multi-lock autoinhibition mechanism as that utilized by WWP1, whereas Nedd4/4 L and Smurf2 utilize a slightly variant version. Overall, these results reveal versatile autoinhibitory mechanisms that fine-tune the ligase activities of the HECT family enzymes.

Date: 2019
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-019-11224-7 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11224-7

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-11224-7

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().