PMID- 10196129
OWN - NLM
STAT- MEDLINE
DCOM- 19990610
LR  - 20190915
IS  - 0969-2126 (Print)
IS  - 0969-2126 (Linking)
VI  - 7
IP  - 4
DP  - 1999 Apr 15
TI  - Structure of the PH domain from Bruton's tyrosine kinase in complex with inositol
      1,3,4,5-tetrakisphosphate.
PG  - 449-60
AB  - 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.
FAU - Baraldi, E
AU  - Baraldi E
AD  - European Molecular Biology Laboratory, Meyerhofstrasse 1, Postfach 102209,
      D-69012 Heidelberg, Germany.
FAU - Djinovic Carugo, K
AU  - Djinovic Carugo K
FAU - Hyvonen, M
AU  - Hyvonen M
FAU - Surdo, P L
AU  - Surdo PL
FAU - Riley, A M
AU  - Riley AM
FAU - Potter, B V
AU  - Potter BV
FAU - O'Brien, R
AU  - O'Brien R
FAU - Ladbury, J E
AU  - Ladbury JE
FAU - Saraste, M
AU  - Saraste M
LA  - eng
SI  - PDB/1B55
SI  - PDB/1BWN
GR  - Wellcome Trust/United Kingdom
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Structure
JT  - Structure (London, England : 1993)
JID - 101087697
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)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (Agammaglobulinaemia Tyrosine Kinase)
RN  - EC 2.7.10.2 (BTK protein, human)
SB  - IM
MH  - Agammaglobulinaemia Tyrosine Kinase
MH  - Agammaglobulinemia/enzymology/genetics
MH  - Amino Acid Sequence
MH  - Amino Acid Substitution
MH  - Calorimetry
MH  - Crystallography, X-Ray
MH  - Dimerization
MH  - Humans
MH  - Inositol Phosphates/*metabolism
MH  - Membrane Lipids/metabolism
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Phosphatidylinositols/metabolism
MH  - *Point Mutation
MH  - *Protein Structure, Tertiary
MH  - Protein-Tyrosine Kinases/*chemistry/deficiency/genetics/metabolism
MH  - Recombinant Fusion Proteins/chemistry/metabolism
MH  - Sequence Alignment
MH  - Sequence Homology, Amino Acid
MH  - Structure-Activity Relationship
MH  - Substrate Specificity
MH  - X Chromosome/genetics
EDAT- 1999/04/10 02:02
MHDA- 2000/04/01 09:00
CRDT- 1999/04/10 02:02
PHST- 1999/04/10 02:02 [pubmed]
PHST- 2000/04/01 09:00 [medline]
PHST- 1999/04/10 02:02 [entrez]
AID - S0969-2126(99)80057-4 [pii]
AID - 10.1016/s0969-2126(99)80057-4 [doi]
PST - ppublish
SO  - Structure. 1999 Apr 15;7(4):449-60. doi: 10.1016/s0969-2126(99)80057-4.