Many fundamental cellular processes are controlled via assembly of a network of proteins at membrane surfaces. The proper recruitment of proteins to membranes can be controlled by a wide variety of mechanisms, including protein lipidation, protein-protein interactions, posttranslational modifications, and binding to specific lipid species present in membranes. There are, however, only a limited number of analytical techniques that can study the assembly of protein-membrane complexes at the molecular level. A relatively new addition to the set of techniques available to study these protein-membrane systems is the use of hydrogen-deuterium exchange mass spectrometry (HDX-MS). HDX-MS experiments measure protein conformational dynamics in their native state, based on the rate of exchange of amide hydrogens with solvent. This review discusses the use of HDX-MS as a tool to identify the interfaces of proteins with membranes and membrane-associated proteins, as well as define conformational changes elicited by membrane recruitment. Specific examples will focus on the use of HDX-MS to examine how large macromolecular protein complexes are recruited and activated on membranes, and how both posttranslational modifications and cancer-linked oncogenic mutations affect these processes.
Keywords: Allosteric modifications; Biophysics; Conformational changes; Fluorescence-resonance energy transfer; GPCR; Hydrogen–deuterium exchange mass spectrometry; Lipid signaling; Membrane proteins; PI3K; Phosphoinositides; Phospholipids; Protein dynamics; Protein–membrane interactions.
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