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Structural insights into enzyme regulation for inositol 1,4,5-trisphosphate 3-kinase B

Academic Article
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Overview

authors

  • Chamberlain, P. P.
  • Sandberg, M. L.
  • Sauer, Karsten
  • Cooke, M. P.
  • Lesley, Scott
  • Spraggon, G.

publication date

  • November 2005

journal

  • Biochemistry  Journal

abstract

  • D-Myoinositol 1,4,5-trisphophate 3-kinases (IP(3)-3Ks) play important roles in metazoan cellular signaling. It has been demonstrated that mice without a functional version of IP(3)-3K isoform B are deficient in peripheral T-cells, indicating that IP(3)-3KB is essential to the developing immune system. The recent apo IP(3)-3KA structure exhibited a helix at the catalytic domain N-terminus exhibited a helix at the N-terminus of the catalytic domain, with a tryptophan indole moiety mimicking the binding mode of the substrate ATP purine ring, suggesting a mechanism of autoinhibition. Here we present the structure of the complete catalytic domain of IP(3)-3KB, including the CaM binding domain in complex with Mg(2+) and ATP. The crystal structure reveals a homodimeric arrangement of IP(3)-3KB catalytic domains, mediated via an intermolecular antiparallel beta-sheet formed from part of the CaM binding region. Residues from the putative autoinhibitory helix are rearranged into a loop configuration, with extensive interactions with the bound ATP. Mutagenesis of residues from this region reveals that substitution of the putative autoinhibitory tryptophan generates a hyperactive enzyme which retains Ca(2+)/CaM sensitivity. The IP(3)-3KB structure suggests a mechanism of enzyme activation, and raises the possibility that an interaction between IP(3)-3KB molecules may occur as part of the catalytic or regulatory cycle.

subject areas

  • Adenosine Triphosphate
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • Enzyme Activation
  • Humans
  • Magnesium
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Phosphotransferases (Alcohol Group Acceptor)
  • Protein Conformation
  • Protein Isoforms
  • Sequence Alignment
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Identity

International Standard Serial Number (ISSN)

  • 0006-2960

Digital Object Identifier (DOI)

  • 10.1021/bi051256q

PubMed ID

  • 16262249
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Additional Document Info

start page

  • 14486

end page

  • 14493

volume

  • 44

issue

  • 44

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