7SYF

Reconstruction of full-length Prex-1 (PtdIns(3,4,5)P3-dependent Rac Exchanger 1)

Summary for 7SYF

• Entry DOI: 10.2210/pdb7syf/pdb
• EMDB information: 25524 25525 25526
• Descriptor: Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein,Endolysin chimera (1 entity in total)
• Functional Keywords: guanine nucleotide exchange factor, metastasis, plasma membrane, rho gtpase signalling, oncoprotein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 191462.98

Authors

Lupton, C.J.,Bayly-Jones, C.,Ellisdon, A.M. (deposition date: 2021-11-24, release date: 2022-07-27, Last modification date: 2024-02-28)

Primary citation

Chang, Y.G.,Lupton, C.J.,Bayly-Jones, C.,Keen, A.C.,D'Andrea, L.,Lucato, C.M.,Steele, J.R.,Venugopal, H.,Schittenhelm, R.B.,Whisstock, J.C.,Halls, M.L.,Ellisdon, A.M.
Structure of the metastatic factor P-Rex1 reveals a two-layered autoinhibitory mechanism.
Nat.Struct.Mol.Biol., 29:767-773, 2022

PubMed Abstract: 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.

PubMed: 35864164
DOI: 10.1038/s41594-022-00804-9

Experimental method

ELECTRON MICROSCOPY (4.2 Å)