Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

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

Chamberlain, Philip, Sandberg, Mark, Sauer, Karsten, Cooke, Michael, Lesley, Scott and Spraggon, Glen (2005) Structural insights into enzyme regulation for inositol 1,4,5-trisphosphate 3-kinase B. Biochemistry, 44 (44). pp. 14486-14493. ISSN 0006-2960


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.

Item Type: Article
Related URLs:
Additional Information: archiving not formally supported by this publisher
Related URLs:
Date Deposited: 14 Dec 2009 14:02
Last Modified: 31 Jan 2013 01:23


Email Alerts

Register with OAK to receive email alerts for saved searches.