Unraveling the molecular mechanism of interactions of the Rho GTPases Cdc42 and Rac1 with the scaffolding protein IQGAP2.

摘要: IQ motif-containing GTPase-activating proteins (IQGAPs) are scaffolding playing central roles in cell-cell adhesion, polarity, and motility. The Rho GTPases Cdc42 Rac1, their GTP-bound active forms, interact with all three human IQGAPs. IQGAP-Cdc42 interaction promotes metastasis by enhancing actin polymerization. However, despite high sequence identity, Rac1 differ interactions IQGAP. Two molecules can bind to the Ex-domain RasGAP site of protein (GAP)-related domain (GRD) IQGAP promote dimerization. Only one molecule might GRD may not facilitate dimerization, exact mechanism binding is unclear. Using all-atom molecular dynamics simulations, site-directed mutagenesis, Western blotting, we unraveled detailed mechanisms IQGAP2. We observed that IQGAP2 (GRD2) releases at C-terminal region GRD2, facilitating promoted allosteric changes site, providing a for second site. Of note, "insert loop" was important first Ex-domain. By contrast, differences insert-loop structure precluded its could only apo-GRD2 Our mechanistic insights help decipher how stimulate polymerization metastasis.