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The iSH2 domain of PI 3-kinase is a rigid tether for p110 and not a conformational switch

, : The iSH2 domain of PI 3-kinase is a rigid tether for p110 and not a conformational switch. Archives of Biochemistry and Biophysics 432(2): 244-251

Class IA PI 3-kinases are heterodimeric proteins with distinct catalytic (p110) and regulatory (p85) subunits. The minimal fragment of p85 capable of regulating p110 activity (p85ni) is the N-terminal SH2 domain linked to the iSH2 coiled-coil domain. We used cysteine mutagenesis and 14C-NEM-labeling to show that the p110-binding site in the iSH2 domain includes two regions: residues 482-484 and 532-541. These regions are adjacent to each other in the three-dimensional structural model of the iSH2 domain, and define a coherent binding site. We then used spin labeling and EPR spectroscopy to demonstrate that the conformation of the iSH2 domain is unaffected by binding to the N-terminal fragment of p110 (residues 1-108), and/or by phosphopeptide binding to p85ni/p110(1-108) heterodimers. Finally, we show that the cSH2 domain cannot substitute for the nSH2 domain with regard to inhibition of p110. These data support a model in which the iSH2 domain is a rigid tether for p110, and regulation of p85/p110 is mediated by nSH2-p110 contacts. Copyright 2004 Elsevier Inc. All rights reserved.


PMID: 15542063

DOI: 10.1016/

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