9ZQ7
Autoinhibited P-Rex2
Summary for 9ZQ7
| Entry DOI | 10.2210/pdb9zq7/pdb |
| EMDB information | 74550 |
| Descriptor | Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 protein (1 entity in total) |
| Functional Keywords | rho guanine-nucleotide exchange factor, autoinhibition, signaling protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 184506.20 |
| Authors | |
| Primary citation | Anderson, L.K.,Marde, R.,Muma, G.,Nayak, V.,Phan, C.,Li, S.,Cash, J.N. The Rho guanine-nucleotide exchange factor P-Rex2 exhibits structural and regulatory features distinct from the related RhoGEF P-Rex1. J.Biol.Chem., 302:113229-113229, 2026 Cited by PubMed Abstract: Rho guanine-nucleotide exchange factors (RhoGEFs) activate small GTPases to drive cytoskeletal rearrangement, cell motility, and proliferation. The phosphatidylinositol-3,4,5-trisphosphate (PIP)-dependent Rac exchanger (P-Rex) subfamily of RhoGEFs includes P-Rex1 and P-Rex2 which, when misregulated, contribute to cancer progression and metastasis. P-Rex activity is controlled by accessory domains that maintain the protein in a cytosolic, autoinhibited state until activated by the lipid PIP and G protein βγ subunits. While P-Rex1 autoinhibition has been structurally and biochemically characterized, P-Rex2 has remained largely unexplored. Furthermore, despite high sequence similarity and domain conservation, P-Rex homologs differ in substrate specificity and regulatory interactions, and the molecular basis for these divergences is unknown. Here, we have taken an integrative structural biology approach to investigate these gaps. Using cryo-EM, we determined the first structure of full-length P-Rex2 to moderate resolution, revealing that, while the overall structure closely resembles that of P-Rex1, there is a substantial repositioning of the N-terminal module relative to the C-terminal core. This may play a key role in precluding the intramolecular interactions between the N- and C-terminal domains that are observed in autoinhibited P-Rex1. Hydrogen-deuterium exchange mass spectrometry revealed that, unlike P-Rex1, P-Rex2 dynamics are unaffected by IP, the headgroup of PIP. SEC-SAXS data support that the N-terminal module itself is less dynamic, and biochemical assays show that P-Rex2 may be differently regulated by autoinhibition, likely through a mechanism divergent from P-Rex1. These findings uncover unique features in the molecular mechanisms of P-Rex2 regulation. PubMed: 42248461DOI: 10.1016/j.jbc.2026.113229 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (5.2 Å) |
Structure validation
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