Lipids as determinants of membrane protein folding and topological organization

Lipids are recognized as the molecules that define the barrier properties of membranes. Considerable evidence has established that lipids are more than the solvent within which membrane proteins fold and function. Specific lipids directly influence membrane protein folding and topology. Using a molecular genetic approach to systematically alter the phospholipid composition of the Escherichia coli membrane and a biochemical approach to monitor the topological organization of well‐characterized membrane proteins, several secondary solute transport proteins have been demonstrated to be dependent on phosphatidylethanolamine (PE) for their proper topology and function. Re‐introduction of PE post‐assembly of these proteins restores native properties of the transporters. Replacement of PE by foreign lipids that differ structurally with but exhibit similar physical and chemical properties to PE restores both proper topology and function, which supports common functions for lipids with diverse structures. Changes in membrane lipid composition have dramatic and reversible effects on membrane protein topology and function, which have profound implications for the regulation of protein function in eukaryotic cells where the local lipid environment of membrane proteins changes within a membrane and during movement of proteins via the vesicular trafficking system. Elucidation of the relationship between topogenic signals within the amino acid sequence of membrane proteins and the lipid environment as a topological determinant will lead to a better understanding of diseases that result from misfolding of membrane proteins. Supported by NIH R37 GM20478