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Phosphoinositide‐mimicking peptide sequences are binding targets for PH domains
Author(s) -
Mendrola Jeannine,
Lemmon Mark A
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.873.7
Subject(s) - pleckstrin homology domain , biochemistry , inositol , chemistry , peptide , peptide sequence , binding site , phosphoserine , plasma protein binding , saccharomyces cerevisiae , biology , microbiology and biotechnology , biophysics , yeast , receptor , signal transduction , phosphorylation , gene , serine
Pleckstrin homology (PH) domains are the 11 th most common domain in the human proteome and are best known as phosphoinositide (PI) targeting modules. However, less than 10% of PH domains recognize PIs with high affinity and specificity raising the question of what is the target of the other 90%. We have identified peptides enriched in acidic or phosphoserine residues as potential protein targets for PH domains. Nearly 40% of all S. cerevisiae PH domains were able to recognize the highly acidic protein Nsr1p in pulldown experiments, making this a more common property than high affinity PI binding. We also showed binding of GST‐fusions of PLC‐δ 1 or yeast Boi2p PH domains to a multiphosphorylated peptide of IRBIT with estimated K D values of 0.3μM and 8.4μM respectively. PH domain mutations that disrupted PI binding also abrogated IRBIT binding. We hypothesize that stretches of acidic residues and/or phosphoserines structurally mimic inositol phosphates/phosphoinositide headgroups, and thus bind to at least a subclass of PH domains. Such ' phosphoinositide mimicry ' could represent a previously undescribed molecular recognition mechanism for driving specific PH domain/protein interactions.