How bilayer properties influence membrane protein folding

Abstract

The question of how proteins manage to organize into a unique threedimensional structure has been a major field of study since the first protein structures were determined. For membrane proteins, the question is made more complex because, unlike water-soluble proteins, the solvent is not homogenous or even unique. Each cell and organelle has a distinct lipid composition that can change in response to environmental stimuli. Thus, the study of membrane protein folding requires not only understanding how the unfolded chain navigates its way to the folded state, but also how changes in bilayer properties can affect that search. Here we review what we know so far about the impact of lipid composition on bilayer physical properties and how those properties can affect folding. A better understanding of the lipid bilayer and its effects on membrane protein folding is not only important for a theoretical understanding of the folding process, but can also have a practical impact on our ability to work with and design membrane proteins.

High‐throughput cell‐free screening of eukaryotic membrane protein expression in lipidic mimetics

“…Lipids play a vital role in the folding process, topological organization, and modulation of functionality of membrane proteins. 50,51 This becomes particularly important when studying biophysical and functional characterizations of MPs. 27 Our own data with pyruvate binding to the mitochondrial pyruvate carriers (MPCs) shows that although the MPCs produced with Brij-35 did show binding of pyruvate, the K d s were relatively high, especially for the single MPC proteins, and the binding affinity can probably be improved by synthesizing the MPCs in a lipid bilayer.…”

How physical forces drive the process of helical membrane protein folding

“…The lipid bilayer is an ordered medium and plays an important role in defining membrane protein structure. Indeed, lipid headgroup size and charge, as well as alkyl chain number and length, can alter membrane protein folding, stability, topology, and function (Corin & Bowie, 2020). For example, optimizing lipid chain length to minimize hydrophobic mismatch can enhance protein activity (Lee, 1998; Dumas et al , 2000; Pilot et al , 2001; Hong et al , 2006), likely by affecting helix tilting or packing (Lee, 1998; Pilot et al , 2001).…”

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

“…Their complex folding leads to problems expressing membrane proteins in vitro, making them more difficult to study. Folding studies have investigated the dependence of structure formation on the lipid environment [5][6][7][8][9][10] using full-length protein that has been expressed in cells and purified. Such work has been necessary to probe the mechanistic details including thermodynamics and how the lipid bilayer influences transmembrane (TM) helix insertion and protein folding.…”

“…However, this two-stage model is oversimplistic as not all helices are independently stable [34][35][36][37], and at the time there was limited detailed knowledge of co-translational insertion in vivo (as illustrated in Figure 3). Previous reviews have discussed in depth the energetics and mechanisms of membrane protein folding [34,38], and also the effect of lipids on folding [10]. This review will summarise the effects of lipids on the free energy landscape of alpha-helical membrane protein insertion and folding, using peptides and denaturant studies of full-length proteins.…”