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PDBsum entry 1b55
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structure of the ph domain from bruton'S tyrosine kinase in complex with inositol 1,3,4,5-Tetrakisphosphate.
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Authors
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E.Baraldi,
K.D.Carugo,
M.Hyvönen,
P.L.Surdo,
A.M.Riley,
B.V.Potter,
R.O'Brien,
J.E.Ladbury,
M.Saraste.
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Ref.
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Structure, 1999,
7,
449-460.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Figure 4.
Figure 4. Comparison between the inositol phoshate binding
sites in the (a) Btk PH domain and (b) in the PLC-d PH domain
[31]. Only the residues that are most important for the
interaction are indicated and coloured red and orange. K12 and
R28 in Btk superimpose with K30 and R40 in PLC-d. The
Ins(1,3,4,5)P[4] in Btk and the Ins(1,4,5)P[3]in PLC-d are in
cyan.
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The above figure is
reprinted
by permission from Cell Press:
Structure
(1999,
7,
449-460)
copyright 1999.
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