Abstract
Pleckstrin homology (PH) domains are protein modules of around 120 amino acids found in many proteins involved in cellular signaling. Certain PH domains drive signal-dependent membrane recruitment of their host proteins by binding strongly and specifically to lipid second messengers produced by agonist-stimulated phosphoinositide 3-kinases (PI 3-Ks). We describe X-ray crystal structures of two different PH domains bound to Ins(1,3,4,5)P4, the head group of the major PI 3-K product PtdIns(3,4,5)P3. One of these PH domains (from Grp1) is PtdIns(3,4,5)P3 specific, while the other (from DAPP1/PHISH) binds strongly to both PtdIns(3,4,5)P3 and its 5'-dephosphorylation product, PtdIns(3,4)P2. Comparison of the two structures provides an explanation for the distinct phosphoinositide specificities of the two PH domains and allows us to predict the 3-phosphoinositide selectivity of uncharacterized PH domains.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Amino Acid Sequence
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Binding Sites
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Blood Proteins / chemistry
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Blood Proteins / metabolism
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Crystallography, X-Ray
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Fatty Acids / chemistry
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Fatty Acids / metabolism
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Hydrogen Bonding
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Inositol Phosphates / metabolism*
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Lipoproteins*
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Models, Molecular
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Molecular Sequence Data
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Phosphatidylinositol 3-Kinases / chemistry*
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphatidylinositols / metabolism*
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Protein Structure, Secondary
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Sequence Alignment
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Sequence Homology, Amino Acid
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Signal Transduction
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Substrate Specificity
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src Homology Domains
Substances
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Adaptor Proteins, Signal Transducing
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Blood Proteins
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DAPP1 protein, human
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Fatty Acids
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Inositol Phosphates
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Lipoproteins
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Phosphatidylinositols
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Phosphatidylinositol 3-Kinases
Associated data
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PDB/1FAO
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PDB/1FB8
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PDB/1FHW
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PDB/1FHX