Genome-wide Functional Annotation of Dual-Specificity Protein- and Lipid-Binding Modules that Regulate Protein Interactions

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 domai...

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Veröffentlicht in:Molecular cell 2012-04, Vol.46 (2), p.226-237
Hauptverfasser: Chen, Yong, Sheng, Ren, Källberg, Morten, Silkov, Antonina, Tun, Moe P., Bhardwaj, Nitin, Kurilova, Svetlana, Hall, Randy A., Honig, Barry, Lu, Hui, Cho, Wonhwa
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Sprache:eng
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Zusammenfassung: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. [Display omitted] ► Membrane-binding PDZ domains are identified and classified on a genomic scale ► Many PDZ domains serve as a dual-specificity lipid- and protein-binding module ► Lipid binding of PDZ domains regulates their function by different mechanisms
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2012.02.012