Sorry for the cheesy title, but I’m getting married in a couple of weeks and it is all I can think about (oh, and science of course). I have to admit that I chose a GREAT paper this time!: “Molecular determinants of PI3Kγ-mediated activation downstream of G-protein–coupled receptors” which was published last year in PNAS (1). It is a great example of how people can utilize HDX-MS when they want to understand how the structure of their protein changes as a result of it binding to something else. A lot of times, crystallography cannot address this because the proteins are too big or too dynamic. So when all else fails, turn to mass spec!
The Williams group in Cambridge has spent time pondering the question, “How is PI3Kγ’s activity shaped by association with its p101 adaptor subunit, lipid membranes and G-protein βγ heterodimers?”. First off, let me tell you a little bit about PI3Kγ… this protein is a member of the Class 1B of phosphoinositide-3 kinases (PI3K), whose activation is driven by activation of G-protein coupled receptors (GPCRs) (whereas Class IA PI3K’s are activated by receptor tyrosine kinase (RTK) activation). It is known that upon PI3Kγ activation, the catalytic subunit, p110γ, associates with its regulatory subunit, p101, as well as to the G-protein βγ subunit, resulting in membrane translocation of PI3Kγ… however, the precise mechanisms of these events are unknown. PI3Kγ has many roles in processes such as inflammation, cell migration, cardiac function and wound healing. Increased levels of PI3K products have been associated with several forms of cancers, so this is an important protein to study (2).