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Cell Rep. 2015 Sep 1;12(9):1519-30. doi: 10.1016/j.celrep.2015.07.054. Epub 2015 Aug 20.

Lipid Cooperativity as a General Membrane-Recruitment Principle for PH Domains.

Author information

1
Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany.
2
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.
3
Protein Expression and Purification Core Facility, EMBL, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
4
Cell Biology and Biophysics Unit, EMBL, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
5
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.
6
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.

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.

PMID:
26299969
DOI:
10.1016/j.celrep.2015.07.054
[Indexed for MEDLINE]
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