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.

Protein-enriched outer membrane vesicles as a native platform for outer membrane protein studies

“…This includes the native lipid composition, the lipid membrane asymmetry, and the controlled orientation of membrane proteins, three features, which cannot be accomplished by any reconstitution method. It has been previously shown, that the structure and function of membrane proteins, including Omps, can depend sensitively on the lipid composition, asymmetry and the direction of their insertion into the membrane 4–14 . Such problems are avoided by investigating membrane proteins in their native membrane environment.…”

“…This sensitivity of the fold of membrane proteins to the phospholipid composition of the cytoplasmic membrane is observed frequently 10 . Another intriguing example is the insertion and folding of membrane proteins, which depends on the lipid composition and asymmetry of cellular membranes 11–14 .…”

Single-molecule force spectroscopy of protein-membrane interactions

“…Protein-membrane interactions play pivotal roles in numerous biological processes, including membrane protein folding (Yu et al, 2017;Popot and Engelman, 2016;Min et al, 2015), lipid metabolism and transport (Giordano et al, 2013;Reinisch and De Camilli, 2016;Hammond and Balla, 2015;Wong et al, 2017), membrane trafficking (Zhou et al, 2017;Pérez-Lara et al, 2016;Wu et al, 2017;Hurley, 2006;Shen et al, 2012;McMahon and Gallop, 2005), signal transduction (Dong et al, 2017;Aggarwal and Ha, 2016;Lemmon, 2008;Das et al, 2015), and cell motility (Wang and Ha, 2013;Tsujita and Itoh, 2015). Studying these interactions is often difficult, especially when they involve multiple intermediates, multiple ligands, mechanical force, large energy changes, or protein aggregation (Dong et al, 2017;Pérez-Lara et al, 2016;Arauz et al, 2016).…”

NMR Investigation of Structures of G-protein Coupled Receptor Folding Intermediates

“…A rather surprising recent discovery is that the biological scale for partitioning amino acids between the translocon and the ER membrane (45) is very similar to the biophysical data for partitioning between water and lipid bilayers (17). Perhaps based in part on this finding Popot and Engelman entitled their recent commentary on membrane protein folding "Membranes do not tell proteins how to fold", emphasizing that membrane protein folding is primarily encoded by the amino acid sequence and largely independent of the specifics of the environment as long as it is sufficiently hydrophobic (66). Accordingly, membrane protein folding in their view is also not determined by specific properties of the translocon.…”