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Structure of the PH domain from Bruton's tyrosine kinase in complex with inositol 1,3,4,5-tetrakisphosphate

Baraldi, E; Carugo, KD; Hyvonen, M; Lo Surdo, P; Riley, AM; Potter, BV; O'Brien, R; ... Saraste, M; + view all (1999) Structure of the PH domain from Bruton's tyrosine kinase in complex with inositol 1,3,4,5-tetrakisphosphate. Structure , 7 (4) pp. 449-460.

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Abstract

BACKGROUND: The activity of Bruton's tyrosine kinase (Btk) is important for the maturation of B cells. A variety of point mutations in this enzyme result in a severe human immunodeficiency known as X-linked agammaglobulinemia (XLA). Btk contains a pleckstrin-homology (PH) domain that specifically binds phosphatidylinositol 3,4,5-trisphosphate and, hence, responds to signalling via phosphatidylinositol 3-kinase. Point mutations in the PH domain might abolish membrane binding, preventing signalling via Btk. RESULTS: We have determined the crystal structures of the wild-type PH domain and a gain-of-function mutant E41K in complex with D-myo-inositol 1,3,4,5-tetra-kisphosphate (Ins (1,3,4,5)P4). The inositol Ins (1,3,4,5)P4 binds to a site that is similar to the inositol 1,4,5-trisphosphate binding site in the PH domain of phospholipase C-delta. A second Ins (1,3,4,5)P4 molecule is associated with the domain of the E41K mutant, suggesting a mechanism for its constitutive interaction with membrane. The affinities of Ins (1, 3,4,5)P4 to the wild type (Kd = 40 nM), and several XLA-causing mutants have been measured using isothermal titration calorimetry. CONCLUSIONS: Our data provide an explanation for the specificity and high affinity of the interaction with phosphatidylinositol 3,4,5- trisphosphate and lead to a classification of the XLA mutations that reside in the Btk PH domain. Mis-sense mutations that do not simply destabilize the PH fold either directly affect the interaction with the phosphates of the lipid head group or change electrostatic properties of the lipid-binding site. One point mutation (Q127H) cannot be explained by these facts, suggesting that the PH domain of Btk carries an additional function such as interaction with a Galpha protein

Type: Article
Title: Structure of the PH domain from Bruton's tyrosine kinase in complex with inositol 1,3,4,5-tetrakisphosphate
Additional information: UI - 99216540 LA - Eng RN - EC 2.7.1.- (btk protein) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - 0 (Inositol Phosphates) RN - 0 (Membrane Lipids) RN - 0 (Phosphatidylinositols) RN - 0 (Recombinant Fusion Proteins) RN - 102850-29-3 (inositol-1,3,4,5-tetrakisphosphate) PT - JOURNAL ARTICLE DA - 19990610 IS - 0969-2126 SB - M CY - ENGLAND JC - B31 AA - Author EM - 199908
Keywords: Structure, pH, Tyrosine, Proteins, Protein-Tyrosine Kinase, recombinant, Agammaglobulinemia, Amino Acid Sequence, Amino Acid Substitution, btk protein, Calorimetry, cell, CELLS, chemistry, classification, Comparative Study, Crystallography, X-Ray, deficiency, Dimerization, enzymology, genetics, inositol 1, 5 tetrakisphosphate, Inositol Phosphates, Lipids, Membrane Lipids, metabolism, Models, Molecular, Molecular Biology, Molecular Sequence Data, Mutation, Phosphatidylinositols, Point Mutation, Protein Structure, Tertiary, Protein Tyrosine Kinase, Recombinant Fusion Proteins, Sequence Alignment, Sequence Homology, Amino Acid, Structure-Activity Relationship, Substrate Specificity, Support, Non-U.S.Gov't, X Chromosome, function, ANS
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: http://discovery.ucl.ac.uk/id/eprint/186611
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