Flip-Flopping Membrane Proteins: How the Charge Balance Rule Governs Dynamic Membrane Protein Topology
Transmembrane and lateral phospholipid asymmetries are not absolute as is the case for integral membrane proteins where asymmetry does not have to be actively maintained due to the enormous energy required to flip across the hydrophobic barrier of the membrane. Although the lipid bilayer is widely considered as a non-flipping zone for most proteins, some integral membrane proteins possess the capacity to reversibly reorient themselves during or after insertion if membrane phospholipid composition is changed, the membrane is depolarized or components of the translocon interact with each other during ATP-driven protein substrate translocation. Membrane proteins can be also engineered to flip after assembly if a strong topological retention signal is introduced at the very end of the polypeptide and then removed post-insertionally. Phosphorylation of an extramembrane domain, which alters its charge nature, could also induce post-insertional topological changes. A structural approach for dynamic membrane protein organization is not achievable by X-ray crystallography. Therefore, a set of unique in vivo and in vitro approaches should be used to establish a detailed mechanistic understanding for how lipid-protein interactions govern dynamic membrane protein structure and function. Novel approaches and concepts have been developed to analyze dynamic lipid-protein interactions and mechanisms of membrane protein folding and topogenesis. Such methods have the advantage of probing the dynamics of biological membrane organization, membrane protein structure, and lipid-protein interactions both in vitro and in vivo.
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