Structural basis of 3-phosphoinositide recognition by pleckstrin homology domains.
Lipid second messengers generated by phosphoinositide (PI) 3-kinases regulate diverse cellular functions through interaction with pleckstrin homology (PH) domains in modular signaling proteins. The PH domain of Grp1, a PI 3-kinase-activated exchange factor for Arf GTPases, selectively binds phosphatidylinositol 3,4,5-trisphosphate with high affinity. We have determined the structure of the Grp1 PH domain in the unliganded form and bound to inositol 1,3,4,5-tetraphosphate. A novel mode of phosphoinositide recognition involving a 20-residue insertion within the beta6/beta7 loop explains the unusually high specificity of the Grp1 PH domain and the promiscuous 3-phosphoinositide binding typical of several PH domains including that of protein kinase B. When compared to other PH domains, general determinants of 3-phosphoinositide recognition and specificity can be deduced.
Lietzke
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SE
Program in Molecular Medicine, University of Massachusetts Medical Center, Worcester 01605, USA.
Bose
S
S
Cronin
T
T
Klarlund
J
J
Chawla
A
A
Czech
M P
MP
Lambright
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DG
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001665:Binding Sites; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D007295:Inositol Phosphates / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D018909:src Homology Domains
D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; C040985:phosphatidylinositol receptors; D019869:Phosphatidylinositol 3-Kinases