6L30

Crystal structure of the epithelial cell transforming 2 (ECT2)

Summary for 6L30

• Entry DOI: 10.2210/pdb6l30/pdb
• Descriptor: Protein ECT2 (1 entity in total)
• Functional Keywords: gef, cell cycle
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 80703.52

Authors

Chen, Z.C.,Chen, M.R.,Pan, H.,Sun, L.F.,Shi, P. (deposition date: 2019-10-07, release date: 2020-01-01, Last modification date: 2023-11-22)

Primary citation

Chen, M.,Pan, H.,Sun, L.,Shi, P.,Zhang, Y.,Li, L.,Huang, Y.,Chen, J.,Jiang, P.,Fang, X.,Wu, C.,Chen, Z.
Structure and regulation of human epithelial cell transforming 2 protein.
Proc.Natl.Acad.Sci.USA, 117:1027-1035, 2020

PubMed Abstract: 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. 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.

PubMed: 31888991
DOI: 10.1073/pnas.1913054117

Experimental method

X-RAY DIFFRACTION (2.8 Å)