4YON

P-Rex1:Rac1 complex

Summary for 4YON

• Entry DOI: 10.2210/pdb4yon/pdb
• Descriptor: Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein, Ras-related C3 botulinum toxin substrate 1 (3 entities in total)
• Functional Keywords: protein binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 65538.19

Authors

Lucato, C.M.,Whisstock, J.C.,Ellisdon, A.M. (deposition date: 2015-03-11, release date: 2015-07-01, Last modification date: 2023-09-27)

Primary citation

Lucato, C.M.,Halls, M.L.,Ooms, L.M.,Liu, H.J.,Mitchell, C.A.,Whisstock, J.C.,Ellisdon, A.M.
The Phosphatidylinositol (3,4,5)-Trisphosphate-dependent Rac Exchanger 1Ras-related C3 Botulinum Toxin Substrate 1 (P-Rex1Rac1) Complex Reveals the Basis of Rac1 Activation in Breast Cancer Cells.
J.Biol.Chem., 290:20827-20840, 2015

PubMed Abstract: The P-Rex (phosphatidylinositol (3,4,5)-trisphosphate (PIP3)-dependent Rac exchanger) family (P-Rex1 and P-Rex2) of the Rho guanine nucleotide exchange factors (Rho GEFs) activate Rac GTPases to regulate cell migration, invasion, and metastasis in several human cancers. The family is unique among Rho GEFs, as their activity is regulated by the synergistic binding of PIP3 and Gβγ at the plasma membrane. However, the molecular mechanism of this family of multi-domain proteins remains unclear. We report the 1.95 Å crystal structure of the catalytic P-Rex1 DH-PH tandem domain in complex with its cognate GTPase, Rac1 (Ras-related C3 botulinum toxin substrate-1). Mutations in the P-Rex1·Rac1 interface revealed a critical role for this complex in signaling downstream of receptor tyrosine kinases and G protein-coupled receptors. The structural data indicated that the PIP3/Gβγ binding sites are on the opposite surface and markedly removed from the Rac1 interface, supporting a model whereby P-Rex1 binding to PIP3 and/or Gβγ releases inhibitory C-terminal domains to expose the Rac1 binding site.

PubMed: 26112412
DOI: 10.1074/jbc.M115.660456

Experimental method

X-RAY DIFFRACTION (1.95 Å)