Helix formation and stability in membranes

Abstract

In this article we review current understanding of basic principles for the folding of membrane proteins, focusing on the more abundant alpha-helical class. Membrane proteins, vital to many biological functions and implicated in numerous diseases, fold into their active conformations in the complex environment of the cell bilayer membrane. While many membrane proteins rely on the translocon and chaperone proteins to fold correctly, others can achieve their functional form in the absence of any translation apparatus or other aides. Nevertheless, the spontaneous folding process is not well understood at the molecular level. Recent findings suggest that helix fraying and loop formation may be important for overall structure, dynamics and regulation of function. Several types of membrane helices with ionizable amino acids change their topology with pH. Additionally we note that some peptides, including many that are rich in arginine, and a particular analogue of gramicidin, are able passively to translocate across cell membranes. The findings indicate that a final protein structure in a lipid-bilayer membrane is sequence-based, with lipids contributing to stability and regulation. While much progress has been made toward understanding the folding process for alpha-helical membrane proteins, it remains a work in progress. This article is part of a Special Issue entitled: Emergence of Complex Behavior in Biomembranes edited by Marjorie Longo.

Influence of Lipid Saturation, Hydrophobic Length and Cholesterol on Double‐Arginine‐Containing Helical Peptides in Bilayer Membranes

“…The resulting pattern of [ 2 H]Ala quadrupolar splitting (Dn q )m agnitudesi ndicates the core helix for R 8,16 GWALP23 is significantly tilted to give as imilart ransmembrane orientation in thinner bilayersw ith either saturated C12:0 or C14:0 acyl chains (1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC) or 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)) or unsa-turatedC 16:1 D9 cis acyl chains. [1,[3][4][5]30] Previously we found that introducing as ingle arginine at position1 4i n GWALP23c aused the peptideh elix to rotate by 808 and to increase its tilt by 108 in DOPC bilayers, thus allowingt he arginine to gain access to the aqueous interface of the lipid bilayer. The inclusion of 10-20 mol %c holesterol in DOPC bilayers drives more of the R 8,16 GWALP23 helix population to the membrane surface, thereby allowing both charged arginines accesst ot he interfacial lipid head groups.T he resultss uggest that hydrophobic thickness and cholesterol content are more important than lipid saturationf or the argininep eptide dynamics and helix orientation in lipid membranes.…”

“…[1] Estimated to make up about3 0% of proteins encoded by the human genome, membranep roteins are the target of 50 %o fc urrent marketed drugs and are implicated in aw ide variety of disorders including Alzheimer's andP arkinson's diseases as well as cystic fibrosis. [1] Estimated to make up about3 0% of proteins encoded by the human genome, membranep roteins are the target of 50 %o fc urrent marketed drugs and are implicated in aw ide variety of disorders including Alzheimer's andP arkinson's diseases as well as cystic fibrosis.…”

“…Charge-charge interactions, Membrane proteins are essential for many cell processes yet are more difficult to investigate than soluble proteins. [1,24] For instance, the voltage-gating ability of a potassium channel, KvAP,i sc ompletely lost in 1,2-dioleoyl-snglycero-3-phosphocholine (DOPC)b ilayers containing more than 18 mol %cholesterol. Model peptidess uch as GWALP23 (acetyl-GGALW 5 LAL 8 LALALAL 16 ALW 19 LAGA-amide) can be used to characterizet he influence of specific residues on transmembrane protein domains.…”

Influence of Saturation and Hydrophobic Length of Lipid Bilayers on Twin-Arginine Containing Helical Peptides

“…Membrane proteins play vital roles in numerous cellular processes including cell signaling, ion transport, and enzymedriven processes. [1] Estimated to make up about3 0% of proteins encoded by the human genome, membranep roteins are the target of 50 %o fc urrent marketed drugs and are implicated in aw ide variety of disorders including Alzheimer's andP arkinson's diseases as well as cystic fibrosis. [1,2] Am ore thorough understanding of the basic principles that govern membrane protein folding will improvet he ability to predict membrane protein structures and functions, anda ddress abnormalities.…”

“…[1] Estimated to make up about3 0% of proteins encoded by the human genome, membranep roteins are the target of 50 %o fc urrent marketed drugs and are implicated in aw ide variety of disorders including Alzheimer's andP arkinson's diseases as well as cystic fibrosis. [1,2] Am ore thorough understanding of the basic principles that govern membrane protein folding will improvet he ability to predict membrane protein structures and functions, anda ddress abnormalities. The constraints imposed by the lipid bilayer environment, nevertheless, presentc hallenges for determining the structures and lipid interactions of membrane proteins,r equirements necessary to elucidate disease mechanisms.…”