Proteolytic Maturation
Among the semaphorin superfamily, RON and Met contain a furin protease cleavage site in a loop connecting β-strands 4D and 5A of Sema domain. In contrast, the semaphorins and plexin receptors lack a furin recognition site [68]. The proteolytic maturations of RON and Met are required for their signal transduction activities [4]. In addition, the lysine and arginine-rich furin cleavage site in RON has been identified as one of two consensus nuclear localization signal sequences that may play a role in the transcriptional regulatory function of RON/EGFR complex in human cancer cells [44]. We have determined the structures of single chain and thrombin-cleaved RON Sema-PSI, hoping to gain structural insight into the functional role played by this specific cleavage event. Two structures are identical within the accuracy of the data, and the loop is disordered in both cases. This suggests that the proteolytic maturation of Pro-RON into α and β chains does not induce conformational changes in the RON Sema-PSI; rather it may be involved in MSP-induced homodimerization, and/or facilitate the weak interaction with the MSP α chain. Similarly, the counterpart 9-residue surface-exposed loop of Met is disordered in Met/HGFβ and Met/InlB structures [63], [71]. The equivalent 4D–5A loop without the consensus furin cleavage site in the semaphorins is involved in homodimerization, but not in plexin receptors [62], [67]. Thus, the structural basis for the mechanism of proteolytic maturation, required for RON and Met receptor activation, remains unclear.