Structural basis of the activation of c-MET receptor

Emiko Uchikawa,Xuewu Zhang,Zhiming Chen,Guan-Yu Xiao,Xiao-Chen Bai

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.

Highlights

The c-MET receptor is a receptor tyrosine kinase (RTK) that plays essential roles in normal cell development and motility
We reasoned that introducing a leucine zipper motif to the C-terminus of c-MET927 with a short flexible loop could potentially stabilize the cMET/hepatocyte growth factor (HGF) complex in the active state (Fig. 1a)[23]
Our cryo-EM and functional analyses indicate that the concurrent binding of one HGF to two c-METs by utilizing two completely distinct interfaces leads to c-MET dimerization and activation

Summary

Introduction

The c-MET receptor is a receptor tyrosine kinase (RTK) that plays essential roles in normal cell development and motility. C-MET is initially expressed as a 150 kDa single-chain precursor, which turns into the mature form through the proteolytic cleavage between Arg[307] and Ser[308] by the furin protease[8]. HGF, the ligand of c-MET, is secreted as a single chain 83 kDa precursor protein containing an N-terminal (N) domain, four consecutive kringle (K1–K4) domains, and a serine protease homology (SPH) domain (Fig. 1a). Similar to c-MET, proteolytic cleavage between Arg[494] and Val[495] of HGF generates the α and β subunits (57 and 26 kDa, respectively), which are linked by a disulfide bond between Cys[487] of α-subunit and a. Both of pro-HGF and cleaved HGF can bind to c-MET with high affinity, but only cleaved HGF can activate c-MET signaling, indicating that proteolytic cleavage is critical for HGF-induced c-MET activation[9,10]. It has been further suggested that the proteolytic cleavage of HGF could trigger its structural rearrangement that is likely to be critical for inducing c-MET activation[11,12]

Methods

Results

Conclusion