National Health and Medical Research Council (NHMRC, Australia)
APP1146578
オーストラリア
National Health and Medical Research Council (NHMRC, Australia)
APP1128120
オーストラリア
引用
ジャーナル: Nat Struct Mol Biol / 年: 2022 タイトル: Structure of the metastatic factor P-Rex1 reveals a two-layered autoinhibitory mechanism. 著者: Yong-Gang Chang / Christopher J Lupton / Charles Bayly-Jones / Alastair C Keen / Laura D'Andrea / Christina M Lucato / Joel R Steele / Hari Venugopal / Ralf B Schittenhelm / James C Whisstock ...著者: Yong-Gang Chang / Christopher J Lupton / Charles Bayly-Jones / Alastair C Keen / Laura D'Andrea / Christina M Lucato / Joel R Steele / Hari Venugopal / Ralf B Schittenhelm / James C Whisstock / Michelle L Halls / Andrew M Ellisdon / 要旨: P-Rex (PI(3,4,5)P-dependent Rac exchanger) guanine nucleotide exchange factors potently activate Rho GTPases. P-Rex guanine nucleotide exchange factors are autoinhibited, synergistically activated by ...P-Rex (PI(3,4,5)P-dependent Rac exchanger) guanine nucleotide exchange factors potently activate Rho GTPases. P-Rex guanine nucleotide exchange factors are autoinhibited, synergistically activated by Gβγ and PI(3,4,5)P 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° opening of the DH domain hinge helix. The off-axis position of Gβγ and PI(3,4,5)P binding sites further suggests a counter-rotation of the P-Rex1 halves by 90° facilitates PH domain uncoupling from the four-helix bundle, releasing the autoinhibited DH domain to drive Rho GTPase signaling.