Genome-Wide Identification and Functional Annotation of Dual Specificity Protein- and Lipid-Binding Modules That Modulate Protein Interactions at the Membrane

• Type of Material: Article
• Authors: Yong Chen, University of Illinois; Ren Sheng, University of Illinois; Morten Kaellberg, University of Illinois; Antonina Silkov, Columbia University; Moe P. Tun, University of Illinois; Nitin Bhardwaj, University of Illinois; Svetlana Kurilova, University of Illinois; Randy A Hall, Emory University; Barry Honig, Columbia University; Hui Lu, University of Illinois; Wonhwa Cho, University of Illinois
• Language: English
• Date: 2012-04-27
• Publisher: Elsevier (Cell Press): 12 month embargo
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Elsevier Inc..
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.molcel.2012.02.012
• Title of Journal or Parent Work: Molecular Cell
• ISSN: 1097-2765
• Volume: 46
• Issue: 2
• Start Page: 226
• End Page: 237
• Grant/Funding Information: The work was also supported by the World Class University program R31-2008-000-10105-0 (W.C.) through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology.; M.K. thanks support from FMC Technologies Fund Fellowship.; This work was in part supported by the Chicago Biomedical Consortium with support from The Searl Funds at the Chicago Community Trust and the National Institutes of Health (GM68849).
• Keywords: IDENTIFICATION; HOMOLOGY DOMAIN; PLASMA-MEMBRANE; Life Sciences & Biomedicine; ORGANIZATION; Science & Technology; PREDICTION; Cell Biology; RECOGNITION; LOCALIZATION; PHOSPHOTYROSINE-BINDING; ELECTROSTATICS; Biochemistry & Molecular Biology; PDZ-DOMAIN
• Research Categories: Chemistry, Biochemistry; Health Sciences, Pharmacology; Biophysics, General

Abstract

Emerging evidence indicates that membrane lipids regulate protein networking by directly interacting with protein-interaction domains (PIDs). As a pilot study to identify and functionally annodate lipid-binding PIDs on a genomic scale, we performed experimental and computational studies of PDZ domains. Characterization of 70 PDZ domains showed that ~40% had submicromolar membrane affinity. Using a computational model built from these data, we predicted the membrane-binding properties of 2,000 PDZ domains from 20 species. The accuracy of the prediction was experimentally validated for 26 PDZ domains. We also subdivided lipid-binding PDZ domains into three classes based on the interplay between membrane- and protein-binding sites. For different classes of PDZ domains, lipid binding regulates their protein interactions by different mechanisms. Functional studies of a PDZ domain protein, rhophilin 2, suggest that all classes of lipid-binding PDZ domains serve as genuine dual-specificity modules regulating protein interactions at the membrane under physiological conditions.