1bwn

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spinqualitylabelsall models 1bwn, resolution 2.1Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

PH DOMAIN AND BTK MOTIF FROM BRUTON'S TYROSINE KINASE MUTANT E41K IN COMPLEX WITH INS(1,3,4,5)P4

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

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.

Disease

Known diseases associated with this structure: Agammaglobulinemia, type 1, X-linked OMIM:[300300], XLA and isolated growth hormone deficiency OMIM:[300300]

About this Structure

1BWN is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Transferred entry: 2.7.10.1 and 2.7.10.2, with EC number 2.7.1.112 Known structural/functional Sites: and . Full crystallographic information is available from OCA.

Reference

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, Surdo PL, Riley AM, Potter BV, O'Brien R, Ladbury JE, Saraste M, Structure. 1999 Apr 15;7(4):449-60. PMID:10196129

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