Structural and Functional Insights into the Regulation of P-Rex1, a Key Regulator of Neutrophil Chemotaxis and Cancer Metastasis
P-Rex1, a guanine nucleotide exchange factor (GEF) for Rac, is synergistically activated by PIP3 and Gβγ subunits, but its regulation remains poorly understood. The study reveals that IP4 inhibits P-Rex1 activity by inducing a conformational change where the pleckstrin homology (PH) domain occludes the active site of the Dbl homology (DH) domain, stabilized by interactions between the DEP1 and DH domains, and between the PH domain and a 4-helix bundle subdomain.