2IWL

Structure of the PX Domain of Phosphoinositide 3-Kinase-C2alpha

Summary for 2IWL

• Entry DOI: 10.2210/pdb2iwl/pdb
• Descriptor: PHOSPHATIDYLINOSITOL-4-PHOSPHATE 3-KINASE C2 DOMAIN-CONTAINING ALPHA POLYPEPTIDE, SULFATE ION (3 entities in total)
• Functional Keywords: pi3k, kinase, px domain, transferase, phosphoinositide 3-kinase, phosphorylation, nuclear protein, phosphoinositide
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cell membrane : O00443
• Total number of polymer chains: 1
• Total formula weight: 16754.15

Authors

Karathanassis, D.,Bravo, J.,Williams, R.L. (deposition date: 2006-07-01, release date: 2006-10-18, Last modification date: 2024-05-08)

Primary citation

Stahelin, R.V.,Karathanassis, D.,Bruzik, K.S.,Waterfield, M.D.,Bravo, J.,Williams, R.L.,Cho, W.
Structural and Membrane Binding Analysis of the Phox Homology Domain of Phosphoinositide 3-Kinase- C2{Alpha}.
J.Biol.Chem., 281:39396-, 2006

PubMed Abstract: Phox homology (PX) domains, which have been identified in a variety of proteins involved in cell signaling and membrane trafficking, have been shown to interact with phosphoinositides (PIs) with different affinities and specificities. To elucidate the structural origin of diverse PI specificities of PX domains, we determined the crystal structure of the PX domain from phosphoinositide 3-kinase C2alpha (PI3K-C2alpha), which binds phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)). To delineate the mechanism by which this PX domain interacts with membranes, we measured the membrane binding of the wild type domain and mutants by surface plasmon resonance and monolayer techniques. This PX domain contains a signature PI-binding site that is optimized for PtdIns(4,5)P(2) binding. The membrane binding of the PX domain is initiated by nonspecific electrostatic interactions followed by the membrane penetration of hydrophobic residues. Membrane penetration is specifically enhanced by PtdIns(4,5)P(2). Furthermore, the PX domain displayed significantly higher PtdIns(4,5)P(2) membrane affinity and specificity when compared with the PI3K-C2alpha C2 domain, demonstrating that high affinity PtdIns(4,5)P(2) binding was facilitated by the PX domain in full-length PI3K-C2alpha. Together, these studies provide new structural insight into the diverse PI specificities of PX domains and elucidate the mechanism by which the PI3K-C2alpha PX domain interacts with PtdIns(4,5)P(2)-containing membranes and thereby mediates the membrane recruitment of PI3K-C2alpha.

PubMed: 17038310
DOI: 10.1074/JBC.M607079200

Experimental method

X-RAY DIFFRACTION (2.6 Å)