Structure of Lipid Kinase p110β/p85β Elucidates an Unusual SH2-Domain-Mediated Inhibitory Mechanism

• Published in: Molecular cell Vol. 41; no. 5; pp. 567 - 578
• Main Authors: Zhang, Xuxiao, Vadas, Oscar, Perisic, Olga, Anderson, Karen E., Clark, Jonathan, Hawkins, Phillip T., Stephens, Len R., Williams, Roger L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04-03-2011; Cell Press
• Subjects: Amino Acid Motifs; Animals; Binding Sites; cell growth; Class Ia Phosphatidylinositol 3-Kinase - metabolism; Gene Expression Regulation, Enzymologic; Humans; Hydrogen Bonding; Insecta; Mice; Mutagenesis; Mutation; Phosphorylation; Protein Conformation; Protein Structure, Tertiary; protein subunits; src Homology Domains
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2011.01.026

Phosphoinositide 3-kinases (PI3Ks) are essential for cell growth, migration, and survival. The structure of a p110β/p85β complex identifies an inhibitory function for the C-terminal SH2 domain (cSH2) of the p85 regulatory subunit. Mutagenesis of a cSH2 contact residue activates downstream signaling in cells. This inhibitory contact ties up the C-terminal region of the p110β catalytic subunit, which is essential for lipid kinase activity. In vitro, p110β basal activity is tightly restrained by contacts with three p85 domains: the cSH2, nSH2, and iSH2. RTK phosphopeptides relieve inhibition by nSH2 and cSH2 using completely different mechanisms. The binding site for the RTK's pYXXM motif is exposed on the cSH2, requiring an extended RTK motif to reach and disrupt the inhibitory contact with p110β. This contrasts with the nSH2 where the pY-binding site itself forms the inhibitory contact. This establishes an unusual mechanism by which p85 SH2 domains contribute to RTK signaling specificities.
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► Both nSH2 and cSH2 domains of p85 inhibit basal activity of p110β ► p110β/p85β structure shows cSH2 contacts the C terminus of p110β ► Relief of cSH2 inhibition, unlike nSH2, requires extending beyond the pYXXM motif ► p110β C terminus is critical for phosphorylation of lipids and activation by RTKs