2P0F

ArhGAP9 PH domain in complex with Ins(1,3,5)P3

Summary for 2P0F

• Entry DOI: 10.2210/pdb2p0f/pdb
• Related: 2P0D 2P0H
• Descriptor: Rho GTPase-activating protein 9, PHOSPHATE ION (3 entities in total)
• Functional Keywords: protein-phosphoinositide complex, pleckstrin homology domain, ligand binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 14520.37

Authors

Ceccarelli, D.F.J.,Blasutig, I.,Goudreault, M.,Ruston, J.,Pawson, T.,Sicheri, F. (deposition date: 2007-02-28, release date: 2007-03-27, Last modification date: 2023-08-30)

Primary citation

Ceccarelli, D.F.,Blasutig, I.M.,Goudreault, M.,Li, Z.,Ruston, J.,Pawson, T.,Sicheri, F.
Non-canonical Interaction of Phosphoinositides with Pleckstrin Homology Domains of Tiam1 and ArhGAP9.
J.Biol.Chem., 282:13864-13874, 2007

PubMed Abstract: Pleckstrin homology (PH) domains are phosphoinositide (PI)-binding modules that target proteins to membrane surfaces. Here we define a family of PH domain proteins, including Tiam1 and ArhGAP9, that demonstrates specificity for PI(4,5)P(2), as well as for PI(3,4,5)P(3) and PI(3,4)P(2), the products of PI 3-kinase. These PH domain family members utilize a non-canonical phosphoinositide binding pocket related to that employed by beta-spectrin. Crystal structures of the PH domain of ArhGAP9 in complex with the headgroups of Ins(1,3,4)P(3), Ins(1,4,5)P(3), and Ins(1,3,5)P(3) reveal how two adjacent phosphate positions in PI(3,4)P(2), PI(4,5)P(2), and PI(3,4,5)P(3) are accommodated through flipped conformations of the bound phospholipid. We validate the non-canonical site of phosphoinositide interaction by showing that binding pocket mutations, which disrupt phosphoinositide binding in vitro, also disrupt membrane localization of Tiam1 in cells. We posit that the diversity in PI interaction modes displayed by PH domains contributes to their versatility of use in biological systems.

PubMed: 17339315
DOI: 10.1074/jbc.M700505200

Experimental method

X-RAY DIFFRACTION (1.91 Å)