Structure of the high affinity complex of inositol trisphosphate with a phospholipase C pleckstrin homology domain.
The X-ray crystal structure of the high affinity complex between the pleckstrin homology (PH) domain from rat phospholipase C-delta 1 (PLC-delta 1) and inositol-(1,4,5)-trisphosphate (Ins(1,4,5)P3) has been refined to 1.9 A resolution. The domain fold is similar to others of known structure. Ins(1,4,5)P3 binds on the positively charged face of the electrostatically polarized domain, interacting predominantly with the beta 1/beta 2 and beta 3/beta 4 loops. The 4- and 5-phosphate groups of Ins(1,4,5)P3 interact much more extensively than the 1-phosphate. Two amino acids in the PLC-delta 1 PH domain that contact Ins(1,4,5)P3 have counterparts in the Bruton's tyrosine kinase (Btk) PH domain, where mutational changes cause inherited agammaglobulinemia, suggesting a mechanism for loss of function in Btk mutants. Using electrostatics and varying levels of head-group specificity, PH domains may localize and orient signaling proteins, providing a general membrane targeting and regulatory function.
Ferguson
K M
KM
Department of Chemistry, Yale University, New Haven, Connecticut 06510, USA.
Lemmon
M A
MA
Schlessinger
J
J
Sigler
P B
PB
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001798:Blood Proteins / Q000737:chemistry*; D018360:Crystallography, X-Ray; D015544:Inositol 1,4,5-Trisphosphate / Q000737:chemistry* / Q000378:metabolism; D007527:Isoenzymes / Q000737:chemistry* / Q000378:metabolism; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D051966:Phospholipase C gamma; D010750:Phosphoproteins; D011487:Protein Conformation; D051381:Rats; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013049:Spectrin / Q000737:chemistry; D010738:Type C Phospholipases / Q000737:chemistry* / Q000378:metabolism
D001798:Blood Proteins; D007527:Isoenzymes; D010750:Phosphoproteins; C039077:platelet protein P47; D013049:Spectrin; D015544:Inositol 1,4,5-Trisphosphate; D010738:Type C Phospholipases; D051966:Phospholipase C gamma