title: Lipid Cooperativity as a General Membrane-Recruitment Principle for PH Domains.
abstract: Many cellular processes involve the recruitment of proteins to specific membranes, which are decorated with distinctive lipids that act as docking sites. The phosphoinositides form signaling hubs, and we examine mechanisms underlying recruitment. We applied a physiological, quantitative, liposome microarray-based assay to measure the membrane-binding properties of 91 pleckstrin homology (PH) domains, the most common phosphoinositide-binding target. 10,514 experiments quantified the role of phosphoinositides in membrane recruitment. For most domains examined, the observed binding specificity implied cooperativity with additional signaling lipids. Analyses of PH domains with similar lipid-binding profiles identified a conserved motif, mutations in which-including some found in human cancers-induced discrete changes in binding affinities in vitro and protein mislocalization in vivo. The data set reveals cooperativity as a key mechanism for membrane recruitment and, by enabling the interpretation of disease-associated mutations, suggests avenues for the design of small molecules targeting PH domains.
authors: Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors: Ivana
authors: I
authors: Vonkova
authors: Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany; Cell Biology and Biophysics Unit, EMBL, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors: Antoine-Emmanuel
authors: AE
authors: Saliba
authors: Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors: Samy
authors: S
authors: Deghou
authors: Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors: Kanchan
authors: K
authors: Anand
authors: Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors: Stefano
authors: S
authors: Ceschia
authors: Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors: Tobias
authors: T
authors: Doerks
authors: Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors: Augustinus
authors: A
authors: Galih
authors: Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors: Karl G
authors: KG
authors: Kugler
authors: Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors: Kenji
authors: K
authors: Maeda
authors: Protein Expression and Purification Core Facility, EMBL, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors: Vladimir
authors: V
authors: Rybin
authors: Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors: Vera
authors: V
authors: van Noort
authors: Cell Biology and Biophysics Unit, EMBL, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors: Jan
authors: J
authors: Ellenberg
authors: Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany; Molecular Medicine Partnership Unit, EMBL, Meyerhofstrasse 1, 69117 Heidelberg, Germany. Electronic address: bork@embl.de.
authors: Peer
authors: P
authors: Bork
authors: Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany; Molecular Medicine Partnership Unit, EMBL, Meyerhofstrasse 1, 69117 Heidelberg, Germany. Electronic address: gavin@embl.de.
authors: Anne-Claude
authors: AC
authors: Gavin
mesh_terms: D002462:Cell Membrane / Q000378:metabolism*; D002597:Chaetomium / Q000378:metabolism; D005656:Fungal Proteins / Q000737:chemistry / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D012441:Saccharomyces cerevisiae / Q000378:metabolism
chemical_list: D005656:Fungal Proteins; D010716:Phosphatidylinositols