Structure of the iSH2 domain of human phosphatidylinositol 3-kinase p85ß subunit reveals conformational plasticity in the interhelical turn region.

ABSTRACT

Phosphatidylinositol 3-kinase (PI3K) proteins actively trigger signaling pathways leading to cell growth, proliferation and survival. These proteins have multiple isoforms and consist of a catalytic p110 subunit and a regulatory p85 subunit. The iSH2 domain of the p85ß isoform has been implicated in the binding of nonstructural protein 1 (NS1) of influenza A viruses. Here, the crystal structure of human p85ß iSH2 determined to 3.3 Šresolution is reported. The structure reveals that this domain mainly consists of a coiled-coil motif. Comparison with the published structure of the bovine p85ß iSH2 domain bound to the influenza A virus nonstructural protein 1 indicates that little or no structural change occurs upon complex formation. By comparing this human p85ß iSH2 structure with the bovine p85ß iSH2 domain, which shares 99% sequence identity, and by comparing the multiple conformations observed within the asymmetric unit of the bovine iSH2 structure, it was found that this coiled-coil domain exhibits a certain degree of conformational variability or `plasticity' in the interhelical turn region. It is speculated that this plasticity of p85ß iSH2 may play a role in regulating its functional and molecular-recognition properties.