Structural basis of the activation of c-MET receptor
| Autor: | Xuewu Zhang, Zhiming Chen, Emiko Uchikawa, Guan Yu Xiao, Xiao Chen Bai |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular 0301 basic medicine Gene isoform Protein Conformation Dimer Science General Physics and Astronomy Motility Kinases Ligands Article General Biochemistry Genetics and Molecular Biology Receptor tyrosine kinase Cell Line 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Humans Protein Isoforms Protein Interaction Domains and Motifs Receptor Multidisciplinary biology Heparin Hepatocyte Growth Factor Chemistry Cryoelectron Microscopy Growth factor signalling General Chemistry Proto-Oncogene Proteins c-met Receptors Neurokinin-1 Ligand (biochemistry) Cell biology HEK293 Cells 030104 developmental biology Cancer cell biology.protein Hepatocyte growth factor 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. Activation of c-MET receptor tyrosine kinase involves hepatocyte growth factor (HGF) and glycosaminoglycans, but the molecular mechanism is still under debate. Here, the authors present cryoEM structures of c-MET bound to two HGF splice variants and heparin, revealing the structural basis for c-MET activation. |
| Databáze: | OpenAIRE |
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