How lipids affect the energetics of co-translational alpha helical membrane protein folding

Abstract

Membrane proteins need to fold with precision in order to function correctly, with misfolding potentially leading to disease. The proteins reside within a hydrophobic lipid membrane and must insert into the membrane and fold correctly, generally whilst they are being translated by the ribosome. Favourable and unfavourable free energy contributions are present throughout each stage of insertion and folding. The unfavourable energy cost of transferring peptide bonds into the hydrophobic membrane interior is compensated for by the favourable hydrophobic effect of partitioning a hydrophobic transmembrane alpha-helix into the membrane. Native membranes are composed of many different types of lipids, but how these different lipids influence folding and the associated free energies is not well understood. Altering the lipids in the bilayer is known to affect the probability of transmembrane helix insertion into the membrane, and lipids also affect protein stability and can promote successful folding. This review will summarise the free energy contributions associated with insertion and folding of alpha helical membrane proteins, as well as how lipids can make these processes more or less favourable. We will also discuss the implications of this work for the free energy landscape during the co-translational folding of alpha helical membrane proteins.

Folding speeds of helical membrane proteins

“…The sky-blue particles depict the high viscosity of lipid bilayers that retards the folding transitions. In the barrier height correction, it is assumed that the membrane viscosity in DMPC bicelles and the resultant τ ω estimate are not substantially altered in DMPC/DMPG bicelles (7:3 mol%), since DMPG has the same acyl chain and similar bilayer-forming tendency as DMPC [ 60 , 61 , 67 ]. DMPC, 1,2-dimyristoyl-sn-glycero-3-phosphocholine; DMPG, 1,2-dimyristoyl-sn-glycero-3-phosphorylglycerol.…”

“…The same time scale is also applicable to the speed limit of the reverse unfolding transitions, as a similar τ ω value of ∼20 ms was obtained for helical harpin dissociation [ 32 ]. The viscosity of the DMPC bicelles and the resultant speed limit estimates would not be substantially altered for other lipids with the same acyl chain and similar bilayer-forming tendency, such as DMPG [ 60 , 61 , 67 ]. It should be noted, however, that other membrane mimetics and lipid compositions with different viscosity levels may non-negligibly change the speed limit time scales.…”

Minimal Out-of-Equilibrium Metabolism for Synthetic Cells: A Membrane Perspective

“…Finally, the in vitro transcription-translation of membrane proteins requires coupling to a mechanism (e.g., SecYEG/YidC or equivalent eukaryotic system) for the insertion and folding of functional membrane proteins. Some polytopic membrane proteins have been reported to self-insert in lipid bilayers in vitro without the aid of an insertion machinery such as the Sec translocon (reviewed in ref ). Examples are MraY, an enzyme responsible for cell wall synthesis, , the β1-adrenergic receptor, the MscL mechanosensitive channel, and the lactose permease LacY .…”

In Search of a Molecular View of Peptide–Lipid Interactions in Membranes

“…Finally, the distribution of charged lipids in membranes has a strong influence on the insertion, translocation, and folding of membrane proteins. − To a large extent, the topology of polypeptide chains of integral membrane proteins obeys the positive inside rule , ,− according to which the orientation of an α-helical segment inserted in the membrane is determined by the location of positively charged amino acid residues at the N- or C-terminus of that segment. Cationic residues are favored by a factor of 4 in the cytoplasmic side of membranes .…”