Structural and dynamic changes in P-Rex1 upon activation by PIP₃ and inhibition by IP₄.

ABSTRACT: PIP₃-dependent Rac exchanger 1 (P-Rex1) is abundantly expressed in neutrophils and plays central roles in chemotaxis and cancer metastasis by serving as a guanine-nucleotide exchange factor (GEF) for Rac. The enzyme is synergistically activated by PIP₃ and the heterotrimeric Gβγ subunits, but mechanistic details remain poorly understood. While investigating the regulation of P-Rex1 by PIP₃, we discovered that Ins(1,3,4,5)P₄ (IP₄) inhibits P-Rex1 activity and induces large decreases in backbone dynamics in diverse regions of the protein. Cryo-electron microscopy analysis of the P-Rex1·IP₄ complex revealed a conformation wherein the pleckstrin homology (PH) domain occludes the active site of the Dbl homology (DH) domain. This

SUBMITTER: Ravala SK 

PROVIDER: S-EPMC10515948 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature