期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 290, 期 34, 页码 20827-20840出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.660456
关键词
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资金
- Faculty of Medicine, Nursing, and Health Sciences
- National Health and Medical Research Council of Australia (NHMRC) [APP1062230, APP1044737]
- Australian Postgraduate Award
- Monash Golden Jubilee Postgraduate Research Award
- NHMRC [1061687]
- National Health and Medical Research Council of Australia [1061687] Funding Source: NHMRC
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 andG beta gamma at the plasma membrane. However, the molecular mechanism of this family of multi-domain proteins remains unclear. We report the 1.95 angstrom 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/G beta gamma 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 G beta gamma releases inhibitory C-terminal domains to expose the Rac1 binding site.
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