ArticleThe Biochemical journal2000
Molecular modelling and site-directed mutagenesis of the inositol 1,3,4,5-tetrakisphosphate-binding pleckstrin homology domain from the Ras GTPase-activating protein GAP1IP4BP.
Article in The Biochemical journal, 2000. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Lipid signaling in T-cell development and function.Cold Spring Harbor perspectives in biology · 2010Review
- Regulation of immune cell development through soluble inositol-1,3,4,5-tetrakisphosphate.Nature reviews. Immunology · 2010Review
- Inositol 1,3,4,5-tetrakisphosphate negatively regulates phosphatidylinositol-3,4,5- trisphosphate signaling in neutrophils.Immunity · 2007Article
- Inositol 1,3,4,5-tetrakisphosphate controls proapoptotic Bim gene expression and survival in B cells.Proceedings of the National Academy of Sciences of the United States of America · 2007Article
- GRP1 pleckstrin homology domain: activation parameters and novel search mechanism for rare target lipid.Biochemistry · 2004Article
- Identification of a Ras GTPase-activating protein regulated by receptor-mediated Ca2+ oscillations.The EMBO journal · 2004Article
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5 authors.
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Abstract
GAP1(IP4BP) is a Ras GTPase-activating protein (GAP) that in vitro is regulated by the cytosolic second messenger inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P(4)]. We have studied Ins(1,3,4,5)P(4) binding to GAP1(IP4BP), and shown that the inositol phosphate specificity and binding affinity are similar to Ins(1,3,4,5)P(4) binding to Bruton's tyrosine kinase (Btk), evidence which suggests a similar mechanism for Ins(1,3,4,5)P(4) binding. The crystal structure of the Btk pleckstrin homology (PH) domain in complex with Ins(1,3,4,5)P(4) has shown that the binding site is located in a partially buried pocket between the beta 1/beta 2- and beta 3/beta 4-loops. Many of the residues involved in the binding are conserved in GAP1(IP4BP). Therefore we generated a model of the PH domain of GAP1(IP4BP) in complex with Ins(1,3,4,5)P(4) based on the Btk-Ins(1,3,4,5)P(4) complex crystal structure. This model had the typical PH domain fold, with the proposed binding site modelling well on the Btk structure. The model has been verified by site-directed mutagenesis of various residues in and around the proposed binding site. These mutations have markedly reduced affinity for Ins(1,3,4,5)P(4), indicating a specific and tight fit for the substrate. The model can also be used to explain the specificity of inositol phosphate binding.
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