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How Lipids Affect the Activities of Integral Membrane Proteins

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How Lipids Affect the Activities of Integral Membrane Proteins Biochimica et Biophysica Acta 1666 (2004) 62–87 http://www.elsevier.com/locate/bba Review How lipids affect the activities of integral membrane proteins Anthony G. Lee* Division of Biochemistry and Molecular Biology, School of Biological Sciences, University of Southampton, Southampton SO16 7PX, UK Received 27 February 2004; accepted 28 May 2004 Available online 20 July 2004 Abstract The activities of integral membrane proteins are often affected by the structures of the lipid molecules that surround them in the membrane. One important parameter is the hydrophobic thickness of the lipid bilayer, defined by the lengths of the lipid fatty acyl chains. Membrane proteins are not rigid entities, and deform to ensure good hydrophobic matching to the surrounding lipid bilayer. The structure of the lipid headgroup region is likely to be important in defining the structures of those parts of a membrane protein that are located in the lipid headgroup region. A number of examples are given where the conformation of the headgroup-embedded region of a membrane protein changes during the reaction cycle of the protein; activities of such proteins might be expected to be particularly sensitive to lipid headgroup structure. Differences in hydrogen bonding potential and hydration between the headgroups of phosphatidycholines and phosphatidylethanolamines could be important factors in determining the effects of these lipids on protein activities, as well as any effects related to the tendency of the phosphatidylethanolamines to form a curved, hexagonal HII phase. Effects of lipid structure on protein aggregation and helix–helix interactions are also discussed, as well as the effects of charged lipids on ion concentrations close to the surface of the bilayer. Interpretations of lipid effects in terms of changes in protein volume, lipid free volume, and curvature frustration are also described. Finally, the role of non-annular, or dco-factorT lipids, tightly bound to membrane proteins, is described. D 2004 Elsevier B.V. All rights reserved. Keywords: Lipid–protein interaction; Annular lipid; Hydrophobic mismatch; Membrane structure; Membrane thickness; Lipid headgroup; Non-annular lipid; Integral membrane protein Contents 1. Introduction ............................................................ 63 1.1. Lipids as solvent and lipids as co-factors: annular and non-annular lipid ......................... 64 2. Effects of annular lipids on membrane protein function ...................................... 65 2.1. The importance of the lipid headgroup region....................................... 65 2.2. Hydrophobic thickness .................................................. 69 2.3. Effects of lipid structure on protein aggregation and helix–helix interactions ....................... 72 2.4. Effects of the gel to liquid crystalline phase transition .................................. 72 Abbreviations: GPS, glycerophosphoserine; GPE, glycerophosphoethanolamine; di(C14:0)PC, dimyristoylphosphatidylcholine; di(C14:1)PC, dimyristo- leoylphosphatidylcholine; di(C16:0)PC, dipalmitoylphosphatidylcholine; di(C18:1)PC, dioleoylphosphatidylcholine; di(C22:1)PC, dierucoylphosphatidylcho- line; di(C22:6)PC, di(4,7,10,13,16,19 docosahexaenoyl)phosphatidylcholine; di(C12:0)PE, dilaurylphosphatidylethanolamine; (C16:0,C18:1)PE, 1-palmitoyl- 2-oleoylphosphatidylethanolamine; di(C18:1)PE, dioleoylphosphatidylethanolamine; di(C18:1)PG, dioleoylphosphatidylglycerol; di(C18:1)PS, dioleoylphos- phatidylserine; di(C18:1)PA, dioleoylphosphatidic acid; MscL, mechanosensitive ion channel of large conductance; EcMscL, MscL from E. coli * Tel.: +44 23 8059 4331; fax: +44 23 8059 4459. E-mail address: [email protected]. 0005-2736/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.bbamem.2004.05.012 A.G. Lee / Biochimica et Biophysica Acta 1666 (2004) 62–87 63 2.5. Effects of membrane viscosity ............................................... 73 2.6. Effects of changes in membrane protein volume ..................................... 75 2.7. Effects of lipid free volume ................................................ 76 2.8. Effects of interfacial curvature and elastic strain...................................... 76 2.9. Effects of lateral pressure profile ............................................. 78 2.10. Effects of membrane tension: mechanosensitive ion channels and osmoregulated transporters .............. 79 3. Effects of non-annular lipids on membrane protein function .................................... 80 4. Conclusions. ............................................................ 83 References ................................................................ 83 1. Introduction Crystal structures have been obtained for rat annexin V in the presence of glycerophosphoserine (GPS) and glycer- Integral membrane proteins operate in an environment ophosphoethanolamine (GPE) [1]. The phosphoglycerol made up, in part, by the surrounding lipid bilayer; the backbones of GPS and GPE bind in a similar fashion, but composition of the lipid bilayer must therefore be such as to with significant differences (Fig. 1). The phosphoryl support at least close to optimal functioning for the proteins oxygen coordinates a bound Ca2+ ion, capping the Ca2+ in the membrane. Effects of lipid structure on membrane binding site [1]. In both complexes Ca2+ binding leads to protein function can be described in molecular terms, that is, extrusion of Trp-185 from the core of the protein; insertion in terms of molecular interactions between the lipid and of Trp-185 into the hydrophobic core of the lipid bilayer protein molecules such as hydrophobic effects, hydrogen adds a hydrophobic component to the binding energy. Gly- bonding or charge interactions, or in physical terms, that is, 186 bridges the Ca2+ ion to the phospholipid; its carbonyl in terms of physical properties of the lipid bilayer such as oxygen coordinates the Ca2+ ion and its amide group lipid fluidity, membrane tension, and so on. Although in interacts with the glycerol backbone of the phospholipid some cases it is obvious that a description in molecular analogues. Thr-187 also interacts with the bound Ca2+ ion, terms is required, in others it is not obvious whether a but, whereas in the GPS complex, its –OH group forms a molecular or a physical explanation is most appropriate. hydrogen bond with the serine amino group in GPS, in the Where both molecular and physical explanations are GPE complex the –OH group of Thr-187 is hydrogen available, it is often not clear whether these are actually bonded to a water molecule that, in turn, hydrogen bonds different explanations or just two different ways of saying to a phosphoryl oxygen. A further difference between the the same thing. two complexes is that the GPE headgroup extends along An example where a molecular description is clearly the the molecular surface in the opposite direction to GPS, in a most appropriate is provided by studies of the effect of shallower binding site (Fig. 1). The more extensive lipid structure on the binding of annexins to the surface of interactions observed in the crystal structure with GPS a lipid bilayer. Binding involves Ca2+ ions bridging than with GPE suggests that binding to phosphatidylserine between the protein and the phospholipid headgroups. will be stronger than to phosphatidylethanolamine. This is Fig. 1. Binding of GPS and GPE to annexin V. The binding sites for GPS (A) and GPE (B) are shown. The filled sphere is Ca2+. Some of the residues important for binding are shown in ball-and-stick mode (PDB files 1A8A and 1A8B). 64 A.G. Lee / Biochimica et Biophysica Acta 1666 (2004) 62–87 indeed what is observed. Although annexin V binds to annular lipid could only affect the function of a membrane bilayers of phosphatidylethanolamine [2,3] it binds more protein if the lifetime of a lipid molecule in the annular shell strongly to bilayers containing anionic phospholipids, the around the protein were long compared to the turnover strength of binding decreasing in the order phosphatidic number of the protein. However, this is not so, it does not acidNphosphatidylserineNphosphatidylinositol [2,4–6].In matter which particular lipid molecule is in the annular contrast, annexin V hardly binds to bilayers of phospha- shell; it is only significant that the lipid molecules that are in tidylcholine or sphingomyelin [2,3]. In this case, therefore, the annular shell are in a particular physical state and have a effects of lipid headgroup structure on protein binding can particular effect on the protein. Rapid exchange of the lipids be understood in molecular terms. Although insertion of can average the environment sensed by the lipid but will not annexin V into the lipid headgroup region of the bilayer average the environment sensed by the protein; the environ- must be affected by physical properties of the lipid ment sensed by the protein (the annular lipid) is the same headgroup region such as the lateral pressure, an explan- however fast the lipids exchange. The rate of exchange of ation in such terms would miss the heart of the problem. non-annular lipid with bulk lipid has not yet been For example, binding to bilayers of phosphatidylethanol- determined, but could be relatively slow given the high amine is stronger than to bilayers of phosphatidylcholine specificity of the interaction between non-annular lipid and not because of differences in the physical properties of the the protein. two bilayers but because the phosphatidylcholine
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