Dynamic structural biology at the protein membrane interface




Burke, John E.

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Journal of Biological Chemistry


Since I started doing scientific research, I've been fascinated by the interplay of protein structure and dynamics and how they together mediate protein function. A particular area of interest has been in understanding the mechanistic basis of how lipid-signaling enzymes function on membrane surfaces. In this award lecture article, I will describe my laboratory's studies on the structure and dynamics of lipid-signaling enzymes on membrane surfaces. This is important, as many lipid-signaling enzymes are regulated through dynamic regulatory mechanisms that control their enzymatic activity. This article will discuss my continued enthusiasm in using a synergistic application of hydrogen–deuterium exchange MS (HDX–MS) with other structural biology techniques to probe the mechanistic basis for how membrane-localized signaling enzymes are regulated and how these approaches can be used to understand how they are misregulated in disease. I will discuss specific examples of how we have used HDX–MS to study phosphoinositide kinases and the protein kinase Akt. An important focus will be on a description of how HDX–MS can be used as a powerful tool to optimize the design of constructs for X-ray crystallography and EM. The use of a diverse toolbox of biophysical methods has revealed novel insight into the complex and varied regulatory networks that control the function of lipid-signaling enzymes and enabled unique insight into the mechanics of membrane recruitment.



phosphoinositide, hydrogen-deuterium exchange mass spectrometry, HDX–MSphosphatidylinositide 3-kinase (PI3K), phosphatidylinositol kinase, Akt PKB, protein dynamics, PI3K, PI4K, PI3K/Ak, Akt, lipid signaling


Burke, J. E. (2019). Dynamic structural biology at the protein membrane interface. Journal of Biological Chemistry, 294(11), 3872-3880. https://doi.org/10.1074/jbc.AW118.003236.