Structure and regulation of human epithelial cell transforming 2 protein

Chen, Mengran; Pan, Han; Sun, Lingfei; Shi, Peng; Zhang, Yikan; Li, Le; Huang, Yuxing; Chen, Jianhui; Jiang, Peng; Fang, Xianyang; Wu, Congying; Chen, Zhucheng

doi:10.1073/pnas.1913054117

Title: Structure and regulation of human epithelial cell transforming 2 protein

Journal Article · 30 December 2019 · Proceedings of the National Academy of Sciences of the United States of America

DOI: https://doi.org/10.1073/pnas.1913054117 · OSTI ID:1601858

Chen, Mengran ^[1]; Pan, Han ^[2]; Sun, Lingfei ^[3]; Shi, Peng ^[4]; Zhang, Yikan ^[2]; Li, Le ^[2]; Huang, Yuxing ^[4]; Chen, Jianhui ^[2]; Jiang, Peng ^[2]; Fang, Xianyang ^[2]; Wu, Congying ^[4]; Chen, Zhucheng ^[2]

Tsinghua Univ., Beijing (China); Peking Univ., Beijing (China)
Tsinghua Univ., Beijing (China)
Tsinghua Univ., Beijing (China); Waigaoqiao Free Trade Zone, Shanghai (China)
Peking Univ., Beijing (China)

Epithelial cell transforming 2 (Ect2) protein activates Rho GTPases and controls cytokinesis and many other cellular processes. Dysregulation of Ect2 is associated with various cancers. Here, we report the crystal structure of human Ect2 and complementary mechanistic analyses. The data show the C-terminal PH domain of Ect2 folds back and blocks the canonical RhoA-binding site at the catalytic center of the DH domain, providing a mechanism of Ect2 autoinhibition. Ect2 is activated by binding of GTP-bound RhoA to the PH domain, which suggests an allosteric mechanism of Ect2 activation and a positive-feedback loop reinforcing RhoA signaling. Furthermore this bimodal RhoA binding of Ect2 is unusual and was confirmed with Förster resonance energy transfer (FRET) and hydrogen–deuterium exchange mass spectrometry (HDX-MS) analyses. Several recurrent cancer-associated mutations map to the catalytic and regulatory interfaces, and dysregulate Ect2 in vitro and in vivo. Together, our findings provide mechanistic insights into Ect2 regulation in normal cells and under disease conditions.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Natural Science Foundation of China (NSFC)

Grant/Contract Number:: 2019YFA0508900; 2017YFA0102900; 31570731; 31270762; 31630046

OSTI ID:: 1601858

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 117, Issue 2; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 25 works

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59 BASIC BIOLOGICAL SCIENCES
cytokinesis
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RhoA
cancer
biophysics

Title: Structure and regulation of human epithelial cell transforming 2 protein

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