LIPID AND NUCLEOTIDE-MEDIATED ALLOSTERY IN SIGNALING PROTEINS

Abstract

Lipids are important effectors of integral and peripheral membrane proteins but how this is mediated is unknown. This dissertation elucidates the conformational dynamics of different classes of signaling proteins in the presence of diverse stimuli within a lipid environment by amide hydrogen/deuterium exchange mass spectrometry. Four classes of signaling proteins have been examined: A soluble stress response protein, BipA, which responds to guanine nucleotide ‘alarmones’, a membrane anchored osmosensor and histidine kinase, EnvZ, a transmembrane transporter BetP and a mammalian lipid storage-inducing protein, FITM2. My research has allowed description of specific allosteric relays in each class of signaling protein which serve to allosterically relay changes from the stimulus response site to a distal effector end. The most important insights provided by my research are in showing that lipids far from being inert matrices, actively modulate dynamics and function of embedded and peripherally associated proteins through parallel allosteric pathways.