Title : Crystal structure of the Sema-PSI extracellular domain of human RON receptor tyrosine kinase
Abstract :
Human RON (Recepteur d'Origine Nantais) receptor tyrosine kinase is a cell surface receptor for Macrophage Stimulating Protein ( MSP )
RON mediates signal transduction pathways that regulate cell adhesion, invasion, motility and apoptosis processes
Elevated levels of RON and its alternatively spliced variants are implicated in the progression and metastasis of tumor cells
The binding of MSP α/β heterodimer to the extracellular region of RON receptor induces receptor dimerization and activation by autophosphorylation of the intracellular kinase domains
The ectodomain of RON , containing the ligand recognition and dimerization domains , is composed of a semaphorin ( Sema ), Plexins-Semaphorins-Integrins domain (PSI), and four Immunoglobulins-Plexins-Transcription factor ( IPT ) domains
High affinity association between MSP and RON is mediated by the interaction between MSP β- chain and RON Sema , although RON activation requires intact RON and MSP proteins
Here, we report the structure of RON Sema-PSI Sema-PSI domains at 1.85 Å resolution
RON Sema domain adopts a seven-bladed β-propeller fold, followed by disulfide bond rich, cysteine-knot PSI motif
Comparison with the homologous Met receptor tyrosine kinase reveals that RON Sema-PSI Sema-PSI contains distinguishing secondary structural features
These define the receptors' exclusive selectivity towards their respective ligands, RON for MSP and Met for HGF
The RON Sema-PSI Sema-PSI crystal packing generates a homodimer with interface formed by the Sema domain
Mapping of the dimer interface using the RON homology to Met , MSP homology to Hepatocyte Growth Factor ( HGF ), and the structure of the Met / HGF complex shows the dimer interface overlapping with the putative MSPβ binding site
The crystallographically determined RON Sema- PSI homodimer may represent the dimer assembly that occurs during ligand-independent receptor activation and/or the inhibition of the constitutive activity of RON Δ160 splice variant by the soluble RON splice variant , RON Δ85