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Structural basis of the activation of c-MET receptor

Author

Listed:
  • Emiko Uchikawa

    (University of Texas Southwestern Medical Center)

  • Zhiming Chen

    (University of Texas Southwestern Medical Center
    University of South China)

  • Guan-Yu Xiao

    (University of Texas Southwestern Medical Center
    University of Texas MD Anderson Cancer Center)

  • Xuewu Zhang

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Xiao-chen Bai

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

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.

Suggested Citation

  • Emiko Uchikawa & Zhiming Chen & Guan-Yu Xiao & Xuewu Zhang & Xiao-chen Bai, 2021. "Structural basis of the activation of c-MET receptor," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24367-3
    DOI: 10.1038/s41467-021-24367-3
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    Cited by:

    1. Jian Zhong & Xujia Wu & Yixin Gao & Junju Chen & Maolei Zhang & Huangkai Zhou & Jia Yang & Feizhe Xiao & Xuesong Yang & Nunu Huang & Haoyue Qi & Xiuxing Wang & Fan Bai & Yu Shi & Nu Zhang, 2023. "Circular RNA encoded MET variant promotes glioblastoma tumorigenesis," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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