Structural basis of the activation of c-MET receptor

Emiko Uchikawa, Zhiming Chen, Guan-Yu Xiao, Xuewu Zhang () and Xiao-chen Bai ()
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Emiko Uchikawa: University of Texas Southwestern Medical Center
Zhiming Chen: University of Texas Southwestern Medical Center
Guan-Yu Xiao: University of Texas Southwestern Medical Center
Xuewu Zhang: University of Texas Southwestern Medical Center
Xiao-chen Bai: University of Texas Southwestern Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract The c-MET receptor is a receptor tyrosine kinase (RTK) that plays essential roles in normal cell development and motility. Aberrant activation of c-MET can lead to both tumors growth and metastatic progression of cancer cells. C-MET can be activated by either hepatocyte growth factor (HGF), or its natural isoform NK1. Here, we report the cryo-EM structures of c-MET/HGF and c-MET/NK1 complexes in the active state. The c-MET/HGF complex structure reveals that, by utilizing two distinct interfaces, one HGF molecule is sufficient to induce a specific dimerization mode of c-MET for receptor activation. The binding of heparin as well as a second HGF to the 2:1 c-MET:HGF complex further stabilize this active conformation. Distinct to HGF, NK1 forms a stable dimer, and bridges two c-METs in a symmetrical manner for activation. Collectively, our studies provide structural insights into the activation mechanisms of c-MET, and reveal how two isoforms of the same ligand use dramatically different mechanisms to activate the receptor.

Date: 2021
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DOI: 10.1038/s41467-021-24367-3

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