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The second messenger phosphatidylinositol 3,4,5-trisphosphate
[PtdIns(3,4,5)P(3)] is generated by the action of phosphoinositide 3-kinase (PI
3-kinase), and regulates a plethora of cellular processes. An approach for
dissecting the mechanisms by which these processes are regulated is to identify
proteins that interact specifically with PtdIns(3,4,5)P(3). The pleckstrin
homology (PH) domain has become recognized as the specialized module used by
many proteins to interact with PtdIns(3,4,5)P(3). Recent work has led to the
identification of a putative phosphatidylinositol 3,4,5-trisphosphate-binding
motif (PPBM) at the N-terminal regions of PH domains that interact with this
lipid. We have searched expressed sequence tag databases for novel proteins
containing PH domains possessing a PPBM. Surprisingly, many of the PH domains
that we identified do not bind PtdIns(3,4,5)P(3), but instead possess unexpected
and novel phosphoinositide-binding specificities in vitro. These include
proteins possessing PH domains that interact specifically with PtdIns(3,4)P(2)
[TAPP1 (tandem PH-domain-containing protein-1) and TAPP2], PtdIns4P [FAPP1
(phosphatidylinositol-four-phosphate adaptor protein-1)], PtdIns3P [PEPP1
(phosphatidylinositol-three-phosphate-binding PH-domain protein-1) and AtPH1]
and PtdIns(3,5)P(2) (centaurin-beta2). We have also identified two related
homologues of PEPP1, termed PEPP2 and PEPP3, that may also interact with
PtdIns3P. This study lays the foundation for future work to establish the
phospholipid-binding specificities of these proteins in vivo, and their
physiological role(s).
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