title: Genome-wide functional annotation of dual-specificity protein- and lipid-binding modules that regulate protein interactions.
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.
authors.affiliation: Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.forename: Ren
authors.initials: R
authors.lastname: Sheng
authors.forename: Morten
authors.initials: M
authors.lastname: Källberg
authors.forename: Antonina
authors.initials: A
authors.lastname: Silkov
authors.forename: Moe P
authors.initials: MP
authors.lastname: Tun
authors.forename: Nitin
authors.initials: N
authors.lastname: Bhardwaj
authors.forename: Svetlana
authors.initials: S
authors.lastname: Kurilova
authors.forename: Randy A
authors.initials: RA
authors.lastname: Hall
authors.forename: Barry
authors.initials: B
authors.lastname: Honig
authors.forename: Hui
authors.initials: H
authors.lastname: Lu
authors.forename: Wonhwa
authors.initials: W
authors.lastname: Cho
mesh_terms: D000818:Animals; D003198:Computer Simulation; D016678:Genome; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D054730:Protein Interaction Domains and Motifs; D051381:Rats; D020349:Surface Plasmon Resonance
chemical_list: D008055:Lipids; D008565:Membrane Proteins