Abstract
The products of the phosphoinositide 3‐kianses (PI3Ks) have essential roles in intracellular signalling and sorting. Using X‐ray crystallography and hydrogen/deuterium exchange mass spectrometry (HDX‐MS) have enabled us to understand mechanisms whereby the PI3Ks and the lipid phosphatase PTEN are activated. HDX‐MS has allowed us characterise protein/protein and protein/membrane interactions for states inaccessible to X‐ray crystallography, and it has provided information about the dynamics of structures.Two sites in the intrinsically disordered tail of PTEN have the ability to to switch its substrate specificity from lipid membranes to soluble substrates. The structural mechanism that regulates the enzyme involves the interaction of both the C2 domain and the lipid phosphatase domain with the C‐terminal tail in phosphorylation‐dependent manner.The p110γ/p101 heterodimeric PI3K is activated downstream of GPCRs by association with Gβγ heterodimers, and HDX‐MS has shown that the p110 helical domain is central to this and other PI3K regulatory influences. The p101 regulatory subunit protects the helical domain, while lipid membrane association exposes it. Membrane binding enables the p110γ/p101 heterodimer to engage Gβγ heterodimers on membranes, using both p110 and p101 subunits.The combination of these methods has enabled us to explore regulation of the broad family of enzymes related to PI3Ks.
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