The crystal structure of the phosphatidylinositol 4-kinase II[alpha]

• Published in: EMBO reports Vol. 15; no. 10; p. 1085
• Main Authors: Baumlova, Adriana, Chalupska, Dominika, Roycki, Bartosz, Jovic, Marko, Wisniewski, Eva, Klima, Martin, Dubankova, Anna, Kloer, Daniel P, Nencka, Radim, Balla, Tamas, Boura, Evzen
• Format: Journal Article
• Language: English
• Published: Heidelberg Blackwell Publishing Ltd 01.10.2014
• Subjects: ATP; Crystal structure; Crystallography; Eukaryotes; Kinases; Lipids; Membranes
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.201438841

Phosphoinositides are a class of phospholipids generated by the action of phosphoinositide kinases with key regulatory functions in eukaryotic cells. Here, we present the atomic structure of phosphatidylinositol 4-kinase type II[alpha] (PI4K II[alpha]), in complex with ATP solved by X-ray crystallography at 2.8 Å resolution. The structure revealed a non-typical kinase fold that could be divided into N- and C-lobes with the ATP binding groove located in between. Surprisingly, a second ATP was found in a lateral hydrophobic pocket of the C-lobe. Molecular simulations and mutagenesis analysis revealed the membrane binding mode and the putative function of the hydrophobic pocket. Taken together, our results suggest a mechanism of PI4K II[alpha] recruitment, regulation, and function at the membrane. Synopsis The crystal structure of PI4K II[alpha] reveals its membrane binding mode and highlights a membrane-oriented hydrophobic pocket as a potential allosteric regulatory site. The crystal structure of PI4K II[alpha] was solved at 2.8 Å resolution. The structure highlights important differences between type II and type III PI 4-kinases. Molecular simulation suggests a membrane binding mode that involves a hydrophobic pocket with allosteric regulatory potential. [PUBLICATION ABSTRACT]