6PCV

Single Particle Reconstruction of Phosphatidylinositol (3,4,5) trisphosphate-dependent Rac exchanger 1 bound to G protein beta gamma subunits

Summary for 6PCV

• Entry DOI: 10.2210/pdb6pcv/pdb
• EMDB information: 20308
• Descriptor: Phosphatidylinositol (3,4,5) trisphosphate-dependent Rac exchanger 1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (3 entities in total)
• Functional Keywords: rhogef, g protein, complex, phosphatase fold, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 231484.37

Authors

Cash, J.N.,Cianfrocco, M.A.,Tesmer, J.J.G. (deposition date: 2019-06-18, release date: 2019-10-23, Last modification date: 2024-03-20)

Primary citation

Cash, J.N.,Urata, S.,Li, S.,Ravala, S.K.,Avramova, L.V.,Shost, M.D.,Gutkind, J.S.,Tesmer, J.J.G.,Cianfrocco, M.A.
Cryo-electron microscopy structure and analysis of the P-Rex1-G beta gamma signaling scaffold.
Sci Adv, 5:eaax8855-eaax8855, 2019

PubMed Abstract: PIP-dependent Rac exchanger 1 (P-Rex1) is activated downstream of G protein-coupled receptors to promote neutrophil migration and metastasis. The structure of more than half of the enzyme and its regulatory G protein binding site are unknown. Our 3.2 Å cryo-EM structure of the P-Rex1-Gβγ complex reveals that the carboxyl-terminal half of P-Rex1 adopts a complex fold most similar to those of phosphoinositide phosphatases. Although catalytically inert, the domain coalesces with a DEP domain and two PDZ domains to form an extensive docking site for Gβγ. Hydrogen-deuterium exchange mass spectrometry suggests that Gβγ binding induces allosteric changes in P-Rex1, but functional assays indicate that membrane localization is also required for full activation. Thus, a multidomain assembly is key to the regulation of P-Rex1 by Gβγ and the formation of a membrane-localized scaffold optimized for recruitment of other signaling proteins such as PKA and PTEN.

PubMed: 31663027
DOI: 10.1126/sciadv.aax8855

Experimental method

ELECTRON MICROSCOPY (3.2 Å)