2. Academic Validation
  3. Structural basis of the activation of c-MET receptor

Structural basis of the activation of c-MET receptor

  • Nat Commun. 2021 Jul 1;12(1):4074. doi: 10.1038/s41467-021-24367-3.
Emiko Uchikawa # 1,  Zhiming Chen # 2 3,  Guan-Yu Xiao 2 4,  Xuewu Zhang 5 6,  Xiao-Chen Bai 7 8
Affiliations

Affiliations

  • 1 Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 2 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 3 Hengyang Medical College, University of South China, Hengyang, Hunan, China.
  • 4 Department of Thoracic Head Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5 Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
  • 6 Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
  • 7 Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
  • 8 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
  • # Contributed equally.
PMID: 34210960 DOI: 10.1038/s41467-021-24367-3
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.

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