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Publication Abstract from PubMed

P-Rex (PI(3,4,5)P3-dependent Rac exchanger) guanine nucleotide exchange factors potently activate Rho GTPases. P-Rex guanine nucleotide exchange factors are autoinhibited, synergistically activated by Gbetagamma and PI(3,4,5)P3 binding and dysregulated in cancer. Here, we use X-ray crystallography, cryogenic electron microscopy and crosslinking mass spectrometry to determine the structural basis of human P-Rex1 autoinhibition. P-Rex1 has a bipartite structure of N- and C-terminal modules connected by a C-terminal four-helix bundle that binds the N-terminal Pleckstrin homology (PH) domain. In the N-terminal module, the Dbl homology (DH) domain catalytic surface is occluded by the compact arrangement of the DH-PH-DEP1 domains. Structural analysis reveals a remarkable conformational transition to release autoinhibition, requiring a 126 degrees opening of the DH domain hinge helix. The off-axis position of Gbetagamma and PI(3,4,5)P3 binding sites further suggests a counter-rotation of the P-Rex1 halves by 90 degrees facilitates PH domain uncoupling from the four-helix bundle, releasing the autoinhibited DH domain to drive Rho GTPase signaling.

Structure of the metastatic factor P-Rex1 reveals a two-layered autoinhibitory mechanism.,Chang YG, Lupton CJ, Bayly-Jones C, Keen AC, D'Andrea L, Lucato CM, Steele JR, Venugopal H, Schittenhelm RB, Whisstock JC, Halls ML, Ellisdon AM Nat Struct Mol Biol. 2022 Jul 21. pii: 10.1038/s41594-022-00804-9. doi:, 10.1038/s41594-022-00804-9. PMID:35864164^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.