title: Genome-wide structural analysis reveals novel membrane binding properties of AP180 N-terminal homology (ANTH) domains.
abstract: An increasing number of cytosolic proteins are shown to interact with membrane lipids during diverse cellular processes, but computational prediction of these proteins and their membrane binding behaviors remains challenging. Here, we introduce a new combinatorial computation protocol for systematic and robust functional prediction of membrane-binding proteins through high throughput homology modeling and in-depth calculation of biophysical properties. The approach was applied to the genomic scale identification of the AP180 N-terminal homology (ANTH) domain, one of the modular lipid binding domains, and prediction of their membrane binding properties. Our analysis yielded comprehensive coverage of the ANTH domain family and allowed classification and functional annotation of proteins based on the differences in local structural and biophysical features. Our analysis also identified a group of plant ANTH domains with unique structural features that may confer novel functionalities. Experimental characterization of a representative member of this subfamily confirmed its unique membrane binding mechanism and unprecedented membrane deforming activity. Collectively, these studies suggest that our new computational approach can be applied to genome-wide functional prediction of other lipid binding domains.
authors.affiliation: Department of Pharmacology, Columbia University, New York, New York 11032, USA.
authors.forename: Antonina
authors.initials: A
authors.lastname: Silkov
authors.forename: Youngdae
authors.initials: Y
authors.lastname: Yoon
authors.forename: Hunjoong
authors.initials: H
authors.lastname: Lee
authors.forename: Nikhil
authors.initials: N
authors.lastname: Gokhale
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Adu-Gyamfi
authors.forename: Robert V
authors.initials: RV
authors.lastname: Stahelin
authors.forename: Wonhwa
authors.initials: W
authors.lastname: Cho
authors.forename: Diana
authors.initials: D
authors.lastname: Murray
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D019143:Evolution, Molecular; D055106:Genome-Wide Association Study; D006801:Humans; D034041:Monomeric Clathrin Assembly Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D040681:Structural Homology, Protein
chemical_list: D034041:Monomeric Clathrin Assembly Proteins; C439023:clathrin assembly protein AP180