title: Membranes Do Not Tell Proteins How To Fold.
abstract: Which properties of the membrane environment are essential for the folding and oligomerization of transmembrane proteins? Because the lipids that surround membrane proteins in situ spontaneously organize into bilayers, it may seem intuitive that interactions with the bilayer provide both hydrophobic and topological constraints that help the protein to achieve a stable and functional three-dimensional structure. However, one may wonder whether folding is actually driven by the membrane environment or whether the folded state just reflects an adaptation of integral proteins to the medium in which they function. Also, apart from the overall transmembrane orientation, might the asymmetry inherent in biosynthesis processes cause proteins to fold to out-of-equilibrium, metastable topologies? Which of the features of a bilayer are essential for membrane protein folding, and which are not? To which extent do translocons dictate transmembrane topologies? Recent data show that many membrane proteins fold and oligomerize very efficiently in media that bear little similarity to a membrane, casting doubt on the essentiality of many bilayer constraints. In the following discussion, we argue that some of the features of bilayers may contribute to protein folding, stability and regulation, but they are not required for the basic three-dimensional structure to be achieved. This idea, if correct, would imply that evolution has steered membrane proteins toward an accommodation to biosynthetic pathways and a good fit into their environment, but that their folding is not driven by the latter or dictated by insertion apparatuses. In other words, the three-dimensional structure of membrane proteins is essentially determined by intramolecular interactions and not by bilayer constraints and insertion pathways. Implications are discussed.
authors.affiliation: Centre National de la Recherche Scientifique/Université Paris-7 UMR 7099 , Institut de Biologie Physico-Chimique (FRC 550), 13, rue Pierre-et-Marie-Curie, F-75005 Paris, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Popot
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University , Box 208114, New Haven, Connecticut 06520-8114, United States.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Engelman
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000737:chemistry*; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry; D008563:Membrane Lipids / Q000737:chemistry*; D008565:Membrane Proteins / Q000737:chemistry*; D008958:Models, Molecular; D011487:Protein Conformation; D017510:Protein Folding; D055503:Protein Multimerization
chemical_list: D008051:Lipid Bilayers; D008563:Membrane Lipids; D008565:Membrane Proteins