The Elsevier book-series Advances in Planar Lipid Bilayers and Liposomes, provides a global platform for a broad community of experimental and theoretical researchers studying cell membranes, lipid model membranes and lipid self-assemblies from the micro- to the nanoscale. Planar lipid bilayers are widely studied due to their ubiquity in nature and find their application in the formulation of biomimetic model membranes and in the design of artificial dispersion of liposomes. Moreover, lipids self-assemble into a wide range of other structures including micelles and the liquid crystalline hexagonal and cubic phases. Consensus has been reached that curved membrane phases do play an important role in nature as well, especially in dynamic processes such as vesicles fusion and cell communication. Self-assembled lipid structures have enormous potential as dynamic materials ranging from artificial lipid membranes to cell membranes, from biosensing to controlled drug delivery, from pharmaceutical formulations to novel food products to mention a few. An assortment of chapters in APLBL represents both an original research as well as comprehensives reviews written by world leading experts and young researchers.
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- An assortment of chapters in APLBL represents both an original research as well as comprehensives reviews written by world leading experts and young researchers.
Effect of Lipid Bilayer Composition on Membrane Protein Association
Aiswarya B. Pawar*; Xavier Prasanna*,┼; Durba Sengupta*,┼,1 * CSIR-National Chemical Laboratory, Pune, Maharashtra, India
┼ Academy of Scientific and Innovative Research, Pune, Maharashtra, India
1 Corresponding author: email address: firstname.lastname@example.org
Diverse cellular functions are supported by membrane protein assemblies associated with the cell membrane. Although considered to be protein-mediated, membrane components are now being recognized as critical in modulating and sometime dictating function. This chapter discusses the effect of the lipid bilayer, in particular its composition on membrane protein organization. Computational methods have been successful in quantifying transmembrane protein association and general features of dimerization profiles are explored. Understanding the molecular basis of the interactions has lead to the recognition of the lipophobic effects. These nonspecific effects include those that arise from membrane perturbations and lipid chain packing and have been shown to modulate the energetics as well as the structural characteristics of membrane protein dimerization. In addition, specific interactions arising from direct protein-lipid interactions and protein-cholesterol interactions have been suggested to influence membrane protein association. We summarize here a few examples highlighting the role of the lipid bilayer on membrane protein organization.
Membrane protein association
The cell membrane is the primary barrier for the cell and is involved in the regulation of cellular information networks . In its simplest form, the cell membrane can be considered as a bilayer of lipids exhibiting free lateral diffusion, as suggested by the fluid mosaic model . With advances in experimental techniques, coupled with a better understanding of multicomponent lipid systems, a paradigm shift has been seen in this view of membrane. The cell membrane is no longer considered as a homogenous "sea of lipids" but suggested to exhibit asymmetrical distribution within and across the leaflets . A diverse species of lipids such as saturated and unsaturated phospholipids, glycolipids and sphingolipids as well as cholesterol are present in cell membranes whose composition is dependent on cell type, stress conditions and even cellular age. The complexity in membrane composition is coupled to evidences pointing toward the presence of transient lipid "micro" or perhaps "nanodomains" which differ in composition and physical properties, such as fluidity and thickness . A schematic representation of the cell membrane highlighting these features is shown in Fig. 1. Besides heterogeneity in nature of lipids, the cell membrane hosts a large population of diverse membrane proteins. The most abundant and best-studied membrane proteins which regulate several physiological processes include transmembrane receptors such as receptor tyrosine kinases (RTKs) (represented by the single transmembrane helices in Fig. 1) and G-protein coupled receptors (GPCRs) (corresponding to the multi-transmembrane protein in Fig. 1) [5, 6]. In addition, the cell membrane is intricately associated with the underlying cytoskeletal network  (shown by the green (gray mesh below the membrane in the print version) network in Fig. 1). The role of various membrane components in cellular function and how they interact together to function is still not clearly understood. Figure 1
A schematic representation of the cell membrane depicting the lipid bilayer with various membrane proteins. Phospholipids are depicted with their head groups in orange (gray in the print version) and acyl chains in yellow (light gray in the print version) and glycolipids are shown in deep blue (dark gray in the print version). Cholesterol is shown in cyan with its head group in red (gray in the print version). Single transmembrane proteins of which ErbB2 is a representative member are depicted in magenta (gray in the print version). G-protein coupled receptors (GPCR) are shown as a multi-transmembrane proteins in purple. Peripheral proteins such as the G-proteins are depicted in pink (gray in the print version) and caveolin are depicted in light blue (gray in the print version). The actin cytoskeleton is shown as a green (gray mesh in the print version) lattice beneath the lipid bilayer.
In this chapter, we discuss the interplay between membrane components-proteins, lipids, and cholesterol. The effect of proteins on the surrounding membrane and how in turn the bilayer modulates protein organization has been analyzed using a few interesting examples. We review the contribution of multiscale simulation studies in providing a molecular-level understanding of these processes. Two protein classes, single transmembrane helices that include the ErbB2 family and larger seven transmembrane proteins, GPCRs have been discussed in detail highlighting the membrane effects in protein association. And finally, a simple overview of the energetics of membrane organization is given.
1.1 Role of Membrane Protein Association in Function
Membrane proteins play important roles in several cellular processes and are involved in pathological mechanisms underlying various human diseases . These proteins interact and associate with one another to form large multimers, several of which have physiological roles . In a few cases, association confers function, while in others activity is regulated by their interaction with each other. A classical example involves the growth factor family (ErbB 1-4) belonging to the RTK class of membrane proteins that have been suggested to associate to an active dimer to initiate downstream signaling . These associations are usually transient and the equilibrium between the multimers determines activity. Over expression of ErbB2, presumably leading to increased association have been shown to be oncogenic. Consequently, modulating transmembrane association can modify downstream signaling events and transmembrane peptides targeting ErbB2 have been recently shown to inhibit breast tumor growth and metastasis . Another example of transmembrane association is the GPCR family in which super resolution experimental approaches have confirmed a dynamic equilibrium between various oligomeric species [12, 13]. Although the monomeric species have been shown to be sufficient for function , GPCR dimerization has been suggested to have both organizational and regulatory roles . Since GPCRs represent important drug targets , the ability of these proteins to exist in several oligomeric states presents a new challenge for targeted drug therapy. An dominant role of lipids in shaping membrane-protein structure  and function [18, 19] is emerging, but its contribution to membrane protein organization is still less explored. The need arises to understand membrane protein association and evaluate the factors controlling association.
1.2 Protein Interactions Are Suggested to Be Sequence Dependent
Experimental approaches investigating membrane protein association suggest sequence specificity to be the major factor in driving interaction . Sequence motifs such as the GxxxG motif have been identified as determinants of transmembrane helix association  and unique helical interfaces comprising of these residues have been proposed . However, inhibition of protein association due to mutation of key residues "predicted" to be essential for protein-protein interaction, could be reverted back by a second mutation elsewhere along the transmembrane segment . Further, quantitative estimates of transmembrane helix association  have revealed key differences from the previous estimates in detergent micelles [21, 25] and via indirect in vivo measurements . Related studies have shown that the lipid bilayer modulates association through sequence-independent effects and membrane composition , and fluidity  have been suggested to play important roles in helix association.
Similarly for GPCRs, unique dimer interfaces have been proposed from experimental studies . Crystal structure of oligomeric ß1-adrenergic receptor revealed two distinct dimer conformations, suggesting the presence of multiple dimer interfaces . Importantly, membrane composition has also been reported to influence structural organization of transmembrane proteins [31, 32]. It is becoming increasingly clear that "non-protein" contributions are significant in membrane protein organization. Even with current state-of-art technologies , experimental approaches are limited in their ability to probe the factors governing membrane protein association. The lack of a "molecular" level insight into the structure and underlying thermodynamics arises due to experimental limitations in structural resolution and lower time-scale sampling.
2 Computational Methods to Analyze...