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Membrane targeting by the GRP1 PH domain
Author(s) -
He Ju,
Vora Mohsin,
Stahelin Robert,
Zhang Honglu,
Prestwich Glenn,
Kutateladze Tatiana G.
Publication year - 2008
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.22.1_supplement.1041.1
Subject(s) - pleckstrin homology domain , membrane , biophysics , chemistry , cell membrane , biochemistry , membrane protein , microbiology and biotechnology , plasma protein binding , lipid bilayer , docking (animal) , biology , medicine , nursing
Pleckstrin homology (PH) domains regulate a wide range of biological processes including cell proliferation and survival, signal transduction, membrane trafficking and cytoskeletal rearrangement through binding to phosphoinositide lipids. The PH domain of GRP1 (general receptor for phosphoinositides) binds PI(3,4,5)P3 with high affinity and specificity, however the overall molecular mechanism of membrane recruitment and docking by GRP1 remains unclear. Here we show that the membrane anchoring of the GRP1 PH domain involves the specific recognition of PI(3,4,5)P3, which is facilitated by non‐specific electrostatic interactions with acidic lipids and accompanied by a hydrophobic insertion into the bilayer. Our data indicate that the association of the GRP1 PH domain with membranes is regulated by the acidic cellular environment. The membrane insertion interfaces, binding parameters and regulation of the PI(3,4,5)P3 binding by pH are investigated by NMR, liposome binding, monolayer surface tension, and mutagenesis experiments. The functional significance of the pH sensitivity and the effect of acidic and basic media on the phosphoinositide recognition, hydrophobic insertion and non‐specific electrostatic contacts are established.