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J Biol Chem, Vol. 273, Issue 46, 30497-30508, November 13, 1998
From the Pleckstrin homology (PH) domains are
small protein modules involved in recruitment of signaling molecules to
cellular membranes, in some cases by binding specific
phosphoinositides. We describe use of a convenient "dot-blot"
approach to screen 10 different PH domains for those that recognize
particular phosphoinositides. Each PH domain bound phosphoinositides in
the assay, but only two (from phospholipase C-
Specificity and Promiscuity in Phosphoinositide Binding by
Pleckstrin Homology Domains
,
,
,
,
, and
Department of Biochemistry and Biophysics,
and Johnson Research Foundation, University of Pennsylvania School of
Medicine, Philadelphia, Pennsylvania 19104-6089, the ¶ Department
of Cell Biology & Oncology, Istituto di Richerche Farmacologiche
"Mario Negri," Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro
CH, Italy, and the
Department of Pharmacology, New York
University Medical Center, Skirball Institute for Biomolecular
Medicine, New York, New York 10016
1
and Grp1) showed clear specificity for a single species. Using soluble
inositol phosphates, we show that the Grp1 PH domain (originally cloned
on the basis of its phosphatidylinositol 3,4,5-trisphosphate
(PtdIns(3,4,5)P3) binding) binds specifically to
D-myo-inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4) (the PtdIns(3,4,5)P3
headgroup) with KD = 27.3 nM, but binds
D-myo-inositol 1,3,4-trisphosphate
(Ins(1,3,4)P3) or D-myo-inositol
1,4,5-trisphosphate (Ins(1,4,5)P3) over 80-fold more
weakly. We show that this specificity allows localization of the Grp1
PH domain to the plasma membrane of mammalian cells only when
phosphatidylinositol 3-kinase (PI 3-K) is activated. The presence of
three adjacent equatorial phosphate groups was critical for inositol
phosphate binding by the Grp1 PH domain. By contrast, another PH domain
capable of PI 3-K-dependent membrane recruitment (encoded
by EST684797) does not distinguish Ins(1,3,4)P3 from
Ins(1,3,4,5)P3 (binding both with very high affinity),
despite selecting strongly against Ins(1,4,5)P3. The
remaining PH domains tested appear significantly less specific for
particular phosphoinositides. Together with data presented in the
literature, our results suggest that many PH domains bind similarly to
multiple phosphoinositides (and in some cases phosphatidylserine),
and are likely to be regulated in vivo by the most abundant
species to which they bind. Thus, using the same simple approach to
study several PH domains simultaneously, our studies suggest that
highly specific phosphoinositide binding is a characteristic of
relatively few cases.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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