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• W2002996832 abstract "Detergents are invaluable tools for studying membrane proteins. However, these deceptively simple, amphipathic molecules exhibit complex behavior when they self-associate and interact with other molecules. The phase behavior and assembled structures of detergents are markedly influenced not only by their unique chemical and physical properties but also by concentration, ionic conditions, and the presence of other lipids and proteins. In this minireview, we discuss the various aggregate forms detergents assume and some misconceptions about their structure. The distinction between detergents and the membrane lipids that they may (or may not) replace is emphasized in the most recent high resolution structures of membrane proteins. Detergents are clearly friends and foes, but with the knowledge of how they work, we can use the increasing variety of detergents to our advantage. Detergents are invaluable tools for studying membrane proteins. However, these deceptively simple, amphipathic molecules exhibit complex behavior when they self-associate and interact with other molecules. The phase behavior and assembled structures of detergents are markedly influenced not only by their unique chemical and physical properties but also by concentration, ionic conditions, and the presence of other lipids and proteins. In this minireview, we discuss the various aggregate forms detergents assume and some misconceptions about their structure. The distinction between detergents and the membrane lipids that they may (or may not) replace is emphasized in the most recent high resolution structures of membrane proteins. Detergents are clearly friends and foes, but with the knowledge of how they work, we can use the increasing variety of detergents to our advantage. critical micelle concentration protein-detergent complex lower consolute β-d-octyl glucoside upper consolute Over the past decade, our understanding of the structure and function of membrane proteins has advanced significantly as well as how their detailed characterization can be approached experimentally. Detergents have played significant roles in this effort. They serve as tools to isolate, solubilize, and manipulate membrane proteins for subsequent biochemical and physical characterization. Many of the successful methods for reconstituting (1Rigaud J.L. Pitard B. Levy D. Biochim. Biophys. Acta. 1995; 1231: 223-246Crossref PubMed Scopus (398) Google Scholar) and crystallizing (2Garavito R.M. Markovic-Housley Z. Jenkins J.A. J. Crystal Growth. 1986; 76: 701-709Crossref Scopus (67) Google Scholar, 3Garavito R.M. Picot D. Loll P.J. J. Bioenerg. Biomembr. 1995; 28: 13-27Crossref Scopus (106) Google Scholar, 4Kühlbrandt W. Q. Rev. Biophys. 1988; 21: 429-477Crossref PubMed Scopus (136) Google Scholar) membrane proteins rely on the unique behavior of detergents. Although many new detergents are now available for use with membrane proteins, their behavior in solution and in the presence of protein may limit their use with specific experimental techniques. Hence, the choice of detergent and experimental conditions will have an enormous impact on whether a technique can be successfully applied to a specific membrane protein. A clear understanding of basic detergent behavior and of the structure of micelles and protein-detergent complexes is thus crucial for membrane biochemists. In this minireview, we will briefly discuss the basic aspects of detergent physical chemistry that affect membrane proteins and their manipulation in the context of the new information about membrane protein structure and function. The reader is directed to comprehensive reviews by Helenius and Simons (5Helenius A. Simons K. Biochim. Biophys. Acta. 1975; 415: 69-79Crossref Scopus (2399) Google Scholar), Tanford and Reynolds (6Tanford C. Reynolds J.A. Biochim. Biophys. Acta. 1976; 457: 133-170Crossref PubMed Scopus (666) Google Scholar), Helenius et al. (7Helenius A. McCaslin D.R. Fries E. Tanford C. Methods Enzymol. 1979; 56: 734-749Crossref PubMed Scopus (597) Google Scholar), Kühlbrandt (4Kühlbrandt W. Q. Rev. Biophys. 1988; 21: 429-477Crossref PubMed Scopus (136) Google Scholar), and Zulauf (8Zulauf M. Michel H. Crystallization of Membrane Proteins. CRC Press, Inc., Boca Raton, FL1991: 54-71Google Scholar), which cover the action and behavior of detergents from a biochemical viewpoint. Excellent monographs by Tanford (9Tanford C. The Hydrophobic Effect. John Wiley & Sons, Inc., New York1980Google Scholar) and Rosen (10Rosen M.J. Surfactants and Interfacial Phenomena. John Wiley & Sons, Inc., New York1978Google Scholar), as well as a review by Wennerström and Lindman (11Wennerström H. Lindman B. Phys. Reports. 1979; 52: 1-86Crossref Scopus (530) Google Scholar), describe the physical chemistry of detergents and surfactants in detail. Detergents are surface-active molecules that self-associate and bind to hydrophobic surfaces in a concentration-dependent manner (8Zulauf M. Michel H. Crystallization of Membrane Proteins. CRC Press, Inc., Boca Raton, FL1991: 54-71Google Scholar, 10Rosen M.J. Surfactants and Interfacial Phenomena. John Wiley & Sons, Inc., New York1978Google Scholar, 11Wennerström H. Lindman B. Phys. Reports. 1979; 52: 1-86Crossref Scopus (530) Google Scholar). The amphipathic character of detergents is evident in their structures (Fig. 1a), which consist of a polar (or charged) head group and a hydrophobic tail. Most detergents fall into one of three categories depending on the type of head group: ionic (cationic or anionic), nonionic, and zwitterionic. The behavior of a specific detergent is dependent on the character and stereochemistry of the head group and tail. In the broader sense, detergents and lipids are both surfactants. What distinguishes one from the other are the concentration regimes for self-association and the kinds of multimolecular structures each can make. The problem of isolating native membrane proteins from lipid bilayers and then subsequently manipulating them is, in essence, a problem of dealing with mixed surfactant systems. The most common question about detergent use is whether a “magic bullet” detergent exists. The simple answer is no, but successful strategies for detergent use do exist. The key to a successful experiment is to understand how detergents and lipids impact the physical nature of a protein-detergent-lipid complex and its behavior. Detergent monomers in aqueous solutions are involved in two kinds of basic phase transitions. First, monomers can crystallize in aqueous solution (10Rosen M.J. Surfactants and Interfacial Phenomena. John Wiley & Sons, Inc., New York1978Google Scholar), although the majority of detergents used in membrane biochemistry do not (4Kühlbrandt W. Q. Rev. Biophys. 1988; 21: 429-477Crossref PubMed Scopus (136) Google Scholar, 5Helenius A. Simons K. Biochim. Biophys. Acta. 1975; 415: 69-79Crossref Scopus (2399) Google Scholar, 6Tanford C. Reynolds J.A. Biochim. Biophys. Acta. 1976; 457: 133-170Crossref PubMed Scopus (666) Google Scholar, 7Helenius A. McCaslin D.R. Fries E. Tanford C. Methods Enzymol. 1979; 56: 734-749Crossref PubMed Scopus (597) Google Scholar). Second, detergent monomers self-associate to form structures called micelles (8Zulauf M. Michel H. Crystallization of Membrane Proteins. CRC Press, Inc., Boca Raton, FL1991: 54-71Google Scholar, 10Rosen M.J. Surfactants and Interfacial Phenomena. John Wiley & Sons, Inc., New York1978Google Scholar, 11Wennerström H. Lindman B. Phys. Reports. 1979; 52: 1-86Crossref Scopus (530) Google Scholar). At a broad threshold of monomer concentration called the critical micelle concentration (CMC)1 (Fig.1 b), self-association occurs and micelles form. Ideally, the concentration of detergent monomers stays constant above the CMC as more detergent is added to the solution; only the concentration of micelles increases (12Gunnarsson G. Jönsson B. Wennerström H. J. Phys. Chem. 1980; 84: 3114-3121Crossref Scopus (364) Google Scholar). When the concentration exceeds the CMC, a detergent becomes capable of solubilizing hydrophobic and amphipathic molecules, such as lipids, into mixed micelles or micellar aggregates (10Rosen M.J. Surfactants and Interfacial Phenomena. John Wiley & Sons, Inc., New York1978Google Scholar). Moreover, the complete and stable solubilization of many integral membrane proteins generally occurs above the CMC, as the detergent associates with the hydrophobic surfaces of membrane proteins to create water-soluble protein-detergent complexes (PDCs) (13Haneskog L. Andersson L. Brekkan E. Englund A.K. Kameyama K. Liljas L. Greijer E. Fischbarg J. Lundahl P. Biochim. Biophys. Acta. 1996; 1282: 39-47Crossref PubMed Scopus (20) Google Scholar, 14le Maire M. Kwee S. Andersen J. Møller J. Eur. J. Biochem. 1983; 129: 525-532Crossref PubMed Scopus (65) Google Scholar, 15Marone P.A. Thiyagarajan P. Wagner A.M. Tiede D.M. J. Crystal Growth. 1999; 207: 214-225Crossref Scopus (23) Google Scholar). Micellarization is a common phenomenon with many surfactants. The average size and shape of micelles depend on the type, size, and stereochemistry of the surfactant monomer (10Rosen M.J. Surfactants and Interfacial Phenomena. John Wiley & Sons, Inc., New York1978Google Scholar, 11Wennerström H. Lindman B. Phys. Reports. 1979; 52: 1-86Crossref Scopus (530) Google Scholar, 16Mitchell D.J. Tiddy G.J.T. Waring L. Bostock T. McDonald M.P. J. Chem. Soc. Faraday Trans. 1983; 79: 975-1000Crossref Google Scholar) as well as the solvent environment. The size of a micelle can be described by its average molecular weight, hydrodynamic radius, and aggregation number (the average number of monomers per micelle). The physical and chemical characteristics of a detergent determine micelle size and shape as well as the size and shape of the detergent layer on a protein. Detergent monomers are often assumed to form relatively uniform surfaces in micelles and in PDCs. This misconception arises from our simplistic cartoons of spherical micelles, wherein the hydrophobic tails, in a trans configuration, are shown extending toward the center of the micelle (Fig.2a). This geometrically impossible picture (8Zulauf M. Michel H. Crystallization of Membrane Proteins. CRC Press, Inc., Boca Raton, FL1991: 54-71Google Scholar, 9Tanford C. The Hydrophobic Effect. John Wiley & Sons, Inc., New York1980Google Scholar) obscures some important insights into how the size, shape, and behavior of a micelle (or a PDC) are dependent on detergent packing. More realistic pictures of a detergent micelle (Fig.2, b and c) have the hydrophobic tails packing in a much more disorganized but compact fashion (17Bogusz S. Venable R.M. Pastor R.W. J. Phys. Chem. B. 2000; 104: 5462-5470Crossref Scopus (131) Google Scholar, 18Tieleman D.P. van der Spoel D. Berendsen H.J.C. J. Phys. Chem. B. 2000; 104: 6380-6388Crossref Scopus (261) Google Scholar). Two consequences of micelle structure are now clearly evident: 1) the micelle surface is quite rough and heterogeneous in character and 2) not all hydrophobic tails are buried or point toward the center of the micelle. Hence, micelle radii are about 10–30% smaller than the fully extended length of the detergent monomer (8Zulauf M. Michel H. Crystallization of Membrane Proteins. CRC Press, Inc., Boca Raton, FL1991: 54-71Google Scholar), and many of the hydrophobic tails have considerable contact with water and solutes. Moreover, molecular dynamics studies (17Bogusz S. Venable R.M. Pastor R.W. J. Phys. Chem. B. 2000; 104: 5462-5470Crossref Scopus (131) Google Scholar, 18Tieleman D.P. van der Spoel D. Berendsen H.J.C. J. Phys. Chem. B. 2000; 104: 6380-6388Crossref Scopus (261) Google Scholar) also show that micelle shape is very dependent on aggregation number (Fig. 2, b and c) and that the concept of a “spherical” micelle really denotes only an average shape. The concept of a compact, disordered micelle clearly suggests that monomer packing defects could radically affect the size, shape, and behavior of micelles. As lipids, other detergents, or amphipathic solutes are incorporated into the micelles of a pure detergent to form mixed micelles, packing defects may be introduced or, on the other hand, eliminated. By extrapolation, the bound detergents in a PDC are unlikely to be well ordered and efficiently packed. Perhaps the inability of certain detergents to solubilize or stabilize some membrane proteins arises from the unstable, defect-ridden packing of detergent monomers on the surface of the protein. Another misconception is that micelles are static structures of uniform shape. The term monodisperse is often applied to colloidal systems to signify a uniform size and shape of a population of particles. For detergents, monodispersity is better perceived to be alack of detectable heterogeneity in the averagemicelle size and shape (19Menger F.M. Acc. Chem. Res. 1979; 12: 111-117Crossref Scopus (477) Google Scholar). The experimental evidence suggests that micelles are quite fluid and rapidly exchange micellar components with the solvent (10Rosen M.J. Surfactants and Interfacial Phenomena. John Wiley & Sons, Inc., New York1978Google Scholar, 11Wennerström H. Lindman B. Phys. Reports. 1979; 52: 1-86Crossref Scopus (530) Google Scholar, 20Thomas M.J. Pang K. Chen Q. Lyles D. Hantgan R. Waite M. Biochim. Biophys. Acta. 1999; 1417: 144-156Crossref PubMed Scopus (13) Google Scholar, 21Zhou C. Roberts M.F. Biochim. Biophys. Acta. 1997; 1348: 273-286Crossref PubMed Scopus (14) Google Scholar). Micelles of small detergents can exhibit dramatic fluctuations in micellar shape; they can deform, split, and fuse over time (10Rosen M.J. Surfactants and Interfacial Phenomena. John Wiley & Sons, Inc., New York1978Google Scholar, 11Wennerström H. Lindman B. Phys. Reports. 1979; 52: 1-86Crossref Scopus (530) Google Scholar, 17Bogusz S. Venable R.M. Pastor R.W. J. Phys. Chem. B. 2000; 104: 5462-5470Crossref Scopus (131) Google Scholar, 18Tieleman D.P. van der Spoel D. Berendsen H.J.C. J. Phys. Chem. B. 2000; 104: 6380-6388Crossref Scopus (261) Google Scholar). For some detergents, appreciable changes in micelle aggregation number, size, and shape may occur as the total detergent concentration rises (22Nilsson P.-G. Wennerström H. Lindman B. J. Phys. Chem. 1983; 87: 1377-1385Crossref Scopus (313) Google Scholar, 23Zulauf M. Rosenbusch J.P. J. Phys. Chem. 1983; 87: 856-862Crossref Scopus (163) Google Scholar). Changes in micelle shape, from spherical to ellipsoidal or even rodlike, occur with many pure detergents (22Nilsson P.-G. Wennerström H. Lindman B. J. Phys. Chem. 1983; 87: 1377-1385Crossref Scopus (313) Google Scholar, 23Zulauf M. Rosenbusch J.P. J. Phys. Chem. 1983; 87: 856-862Crossref Scopus (163) Google Scholar) but may be even more common when a detergent is mixed with another detergent, lipid, or protein (24Lambert O. Levy D. Ranck J.L. Leblanc G. Rigaud J.L. Biophys. J. 1998; 74: 918-930Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). Self-association and crystallization are only two of many possible phase transitions that surfactant solutions may exhibit (8Zulauf M. Michel H. Crystallization of Membrane Proteins. CRC Press, Inc., Boca Raton, FL1991: 54-71Google Scholar, 10Rosen M.J. Surfactants and Interfacial Phenomena. John Wiley & Sons, Inc., New York1978Google Scholar). Phase diagrams of detergent behavior in aqueous solutions are generally simple for the nonionic detergents with N-alkyl tails of 8 carbons (Fig. 3). Nonionic and zwitterionic detergents with N-alkyl tails of 12 carbons or longer tend to exhibit much more complex phase behaviors (Fig. 3), where some phase changes involve micellar growth and/or fusion to form mesophases with distinct structural properties (8Zulauf M. Michel H. Crystallization of Membrane Proteins. CRC Press, Inc., Boca Raton, FL1991: 54-71Google Scholar, 10Rosen M.J. Surfactants and Interfacial Phenomena. John Wiley & Sons, Inc., New York1978Google Scholar, 16Mitchell D.J. Tiddy G.J.T. Waring L. Bostock T. McDonald M.P. J. Chem. Soc. Faraday Trans. 1983; 79: 975-1000Crossref Google Scholar). One common detergent phenomenon is called the cloud point (8Zulauf M. Michel H. Crystallization of Membrane Proteins. CRC Press, Inc., Boca Raton, FL1991: 54-71Google Scholar, 16Mitchell D.J. Tiddy G.J.T. Waring L. Bostock T. McDonald M.P. J. Chem. Soc. Faraday Trans. 1983; 79: 975-1000Crossref Google Scholar), where a clear, homogeneous detergent solution turns turbid upon heating. The formerly single liquid phase (L1) eventually separates into two immiscible solutions (L1′ + L1“), one detergent-rich and the other detergent-poor. The boundary between the isotropic detergent phase and the co-existence of the two liquid phases (Fig. 3) is called a consolute boundary (8Zulauf M. Michel H. Crystallization of Membrane Proteins. CRC Press, Inc., Boca Raton, FL1991: 54-71Google Scholar, 16Mitchell D.J. Tiddy G.J.T. Waring L. Bostock T. McDonald M.P. J. Chem. Soc. Faraday Trans. 1983; 79: 975-1000Crossref Google Scholar). Bordier (25Bordier C. J. Biol. Chem. 1981; 256: 1604-1609Abstract Full Text PDF PubMed Google Scholar) recognized that this phase phenomenon could be exploited for membrane protein purification, and the technique of detergent phase separation is still used today (26Sivars U. Tjerneld F. Biochim. Biophys. Acta. 2000; 1474: 133-146Crossref PubMed Scopus (90) Google Scholar). The phase transitions exhibited by a particular surfactant are determined by its monomer structure (shape) as well as its chemistry (8Zulauf M. Michel H. Crystallization of Membrane Proteins. CRC Press, Inc., Boca Raton, FL1991: 54-71Google Scholar, 16Mitchell D.J. Tiddy G.J.T. Waring L. Bostock T. McDonald M.P. J. Chem. Soc. Faraday Trans. 1983; 79: 975-1000Crossref Google Scholar), e.g. its ionization state or capacity for hydration. Thus, changes in the solvent environment can also alter the nature of surfactant aggregation (8Zulauf M. Michel H. Crystallization of Membrane Proteins. CRC Press, Inc., Boca Raton, FL1991: 54-71Google Scholar, 27Weckstrom K. FEBS Lett. 1985; 192: 220-224Crossref PubMed Scopus (18) Google Scholar). The mere addition of salts or polar solutes to a detergent solution can radically alter the phase behavior of a detergent system, causing phases to appear well below the relatively high detergent concentrations seen with the pure detergents (8Zulauf M. Michel H. Crystallization of Membrane Proteins. CRC Press, Inc., Boca Raton, FL1991: 54-71Google Scholar, 16Mitchell D.J. Tiddy G.J.T. Waring L. Bostock T. McDonald M.P. J. Chem. Soc. Faraday Trans. 1983; 79: 975-1000Crossref Google Scholar). The cloud point phase separation is a frequent problem during membrane protein crystallization (2Garavito R.M. Markovic-Housley Z. Jenkins J.A. J. Crystal Growth. 1986; 76: 701-709Crossref Scopus (67) Google Scholar, 3Garavito R.M. Picot D. Loll P.J. J. Bioenerg. Biomembr. 1995; 28: 13-27Crossref Scopus (106) Google Scholar, 4Kühlbrandt W. Q. Rev. Biophys. 1988; 21: 429-477Crossref PubMed Scopus (136) Google Scholar) and is easily induced by a number of variables (e.g. detergent type, salt, temperature, and precipitant). For example, the octyl-oligooxyethylene (C8Em) detergents display a lower consolute (LC) boundary (Fig. 3). As the temperature rises, micelles aggregate into clusters (8Zulauf M. Michel H. Crystallization of Membrane Proteins. CRC Press, Inc., Boca Raton, FL1991: 54-71Google Scholar, 23Zulauf M. Rosenbusch J.P. J. Phys. Chem. 1983; 87: 856-862Crossref Scopus (163) Google Scholar) until these clusters phase out to form a new aqueous, detergent-rich phase. The addition of salt also depresses the LC boundary to lower temperatures (8Zulauf M. Michel H. Crystallization of Membrane Proteins. CRC Press, Inc., Boca Raton, FL1991: 54-71Google Scholar, 27Weckstrom K. FEBS Lett. 1985; 192: 220-224Crossref PubMed Scopus (18) Google Scholar). In contrast, the addition of polyethylene glycol to solutions of alkyl glycoside detergents, such as β-d-octyl glucoside (β-OG) and β-d-decyl maltoside, causes an upper consolute (UC) boundary to appear (Fig. 3). The take home lesson is that solution and environmental parameters affect not only the basic detergent phenomenon we rely on (micellarization) but also whether other detergent phases appear or not. What makes understanding surfactant phase phenomena so important to membrane biochemists is that the mere use of detergents with membrane proteins forces us to confront them, from protein isolation to crystallization to reconstitution. How a membrane protein behaves will be influenced by detergent-protein and detergent-detergent interactions, as well as interactions with any remaining lipid. Considering only detergents and lipids, it is known that mixed systemswill not behave like solutions of the pure components (10Rosen M.J. Surfactants and Interfacial Phenomena. John Wiley & Sons, Inc., New York1978Google Scholar,11Wennerström H. Lindman B. Phys. Reports. 1979; 52: 1-86Crossref Scopus (530) Google Scholar). Hence, changes in micelle shape and size, CMC, and phase behavior can all occur and they are not easily predicted, even for simple solutions containing two detergents. The addition of a membrane protein to the mix further complicates matters. The fluidity and packing efficiency of the detergent monomers bound to the protein will affect the behavior and stability of the detergent layer. This may result in poor protein solubility and protein inactivation/aggregation. Thus, detergent behavior, during and after protein extraction from a bilayer, will impact the isolation (13Haneskog L. Andersson L. Brekkan E. Englund A.K. Kameyama K. Liljas L. Greijer E. Fischbarg J. Lundahl P. Biochim. Biophys. Acta. 1996; 1282: 39-47Crossref PubMed Scopus (20) Google Scholar, 14le Maire M. Kwee S. Andersen J. Møller J. Eur. J. Biochem. 1983; 129: 525-532Crossref PubMed Scopus (65) Google Scholar,28Kragh-Hansen U. le Maire M. Moller J.V. Biophys. J. 1998; 75: 2932-2946Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar), characterization (13Haneskog L. Andersson L. Brekkan E. Englund A.K. Kameyama K. Liljas L. Greijer E. Fischbarg J. Lundahl P. Biochim. Biophys. Acta. 1996; 1282: 39-47Crossref PubMed Scopus (20) Google Scholar, 15Marone P.A. Thiyagarajan P. Wagner A.M. Tiede D.M. J. Crystal Growth. 1999; 207: 214-225Crossref Scopus (23) Google Scholar, 29Hitscherich C. Kaplan J. Allaman M. Wiencek J. Loll P.J. Protein Sci. 2000; 9: 1559-1566Crossref PubMed Scopus (60) Google Scholar), and stability (13Haneskog L. Andersson L. Brekkan E. Englund A.K. Kameyama K. Liljas L. Greijer E. Fischbarg J. Lundahl P. Biochim. Biophys. Acta. 1996; 1282: 39-47Crossref PubMed Scopus (20) Google Scholar, 30De Grip W.J. Methods Enzymol. 1982; 81: 256-265Crossref PubMed Scopus (88) Google Scholar) of membrane proteins. When considering the added effects of other solvent components (salt, pH, etc.), seemingly small changes in experimental conditions may give rise to detergent effects not expected from the pure detergent. How detergent behavior impacts the solubility, stability, and structure of PDCs is then important to know. For membrane protein crystallization, an early major emphasis was placed on creating simple, lipid-free PDCs (3Garavito R.M. Picot D. Loll P.J. J. Bioenerg. Biomembr. 1995; 28: 13-27Crossref Scopus (106) Google Scholar, 4Kühlbrandt W. Q. Rev. Biophys. 1988; 21: 429-477Crossref PubMed Scopus (136) Google Scholar), using nonionic detergents that produced small, almost spherical micelles (8Zulauf M. Michel H. Crystallization of Membrane Proteins. CRC Press, Inc., Boca Raton, FL1991: 54-71Google Scholar, 31Timmins P.A. Leonhard M. Weltzien H.U. Wacker T. Welte W. FEBS Lett. 1988; 238: 361-368Crossref Scopus (51) Google Scholar) to control the shape, size, and behavior of the PDC. It was soon recognized that detergent-dependent phase transitions had an enormous impact on crystallization. Unwanted phase behavior could prevent crystal growth (32Garavito R.M. Rosenbusch J.P. Methods Enzymol. 1986; 125: 309-328Crossref PubMed Scopus (152) Google Scholar) and even denature protein (33Michel H. EMBO J. 1982; 1: 1267-1271Crossref PubMed Google Scholar). However, in many cases, crystal growth often occurred as conditions approached an upper or lower consolute phase boundary (3Garavito R.M. Picot D. Loll P.J. J. Bioenerg. Biomembr. 1995; 28: 13-27Crossref Scopus (106) Google Scholar). Since then, much effort has focused on understanding the relationship between detergent-dependent phase behavior of the PDC and crystal growth (15Marone P.A. Thiyagarajan P. Wagner A.M. Tiede D.M. J. Crystal Growth. 1999; 207: 214-225Crossref Scopus (23) Google Scholar, 29Hitscherich C. Kaplan J. Allaman M. Wiencek J. Loll P.J. Protein Sci. 2000; 9: 1559-1566Crossref PubMed Scopus (60) Google Scholar), as well as how the characteristics of the PDC can be altered by different detergents (2Garavito R.M. Markovic-Housley Z. Jenkins J.A. J. Crystal Growth. 1986; 76: 701-709Crossref Scopus (67) Google Scholar, 3Garavito R.M. Picot D. Loll P.J. J. Bioenerg. Biomembr. 1995; 28: 13-27Crossref Scopus (106) Google Scholar, 31Timmins P.A. Leonhard M. Weltzien H.U. Wacker T. Welte W. FEBS Lett. 1988; 238: 361-368Crossref Scopus (51) Google Scholar, 32Garavito R.M. Rosenbusch J.P. Methods Enzymol. 1986; 125: 309-328Crossref PubMed Scopus (152) Google Scholar) and the addition of small, amphiphilic consolutes (15Marone P.A. Thiyagarajan P. Wagner A.M. Tiede D.M. J. Crystal Growth. 1999; 207: 214-225Crossref Scopus (23) Google Scholar, 34Thiyagarajan P. Tiede D.M. J. Phys. Chem. 1994; 98: 10343-10351Crossref Scopus (55) Google Scholar, 35Timmins P.A. Hauk J. Wacker T. Welte W. FEBS Lett. 1991; 280: 115-120Crossref PubMed Scopus (45) Google Scholar). The characterization of membrane protein crystals by single-crystal neutron diffraction and D2O/H2O density matching (36Pebay-Peyroula E. Garavito R.M. Rosenbusch J.P. Zulauf M. Timmins P.A. Structure. 1995; 3: 1051-1059Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 37Penel S. Pebay Peyroula E. Rosenbusch J. Rummel G. Schirmer T. Timmins P.A. Biochimie (Paris). 1998; 80: 543-551Crossref PubMed Scopus (26) Google Scholar, 38Roth M. Arnoux B. Ducruix A. Reiss-Husson F. Biochemistry. 1991; 30: 9403-9413Crossref PubMed Scopus (99) Google Scholar, 39Roth M. Lewitt-Bentley A. Michel H. Deisenhofer J. Huber R. Oesterhelt D. Nature. 1989; 340: 659-662Crossref Scopus (186) Google Scholar) has provided a wealth of information about the shape and structure of a PDC. For example, the structures of OmpF porin fromEscherichia coli in different detergents and crystal forms revealed some interesting aspects about detergent behavior. Pebay-Peyroula et al. (36Pebay-Peyroula E. Garavito R.M. Rosenbusch J.P. Zulauf M. Timmins P.A. Structure. 1995; 3: 1051-1059Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar) studied the tetragonal crystal form of OmpF porin containing decyl-dimethylamine-oxide or β-OG. With decyl-dimethylamine-oxide, the PDC behaved as a “hard surface” complex (see Fig. 2 in Pebay-Peyroula et al. (36Pebay-Peyroula E. Garavito R.M. Rosenbusch J.P. Zulauf M. Timmins P.A. Structure. 1995; 3: 1051-1059Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar)), where the detergent layer appeared as a discrete and continuous torus about the protein. In contrast, the porin·β-OG complex revealed a partial fusion of the detergent torus with its neighbors (see Fig. 6 in Pebay-Peyroula et al. (36Pebay-Peyroula E. Garavito R.M. Rosenbusch J.P. Zulauf M. Timmins P.A. Structure. 1995; 3: 1051-1059Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar)). When Penel et al.(37Penel S. Pebay Peyroula E. Rosenbusch J. Rummel G. Schirmer T. Timmins P.A. Biochimie (Paris). 1998; 80: 543-551Crossref PubMed Scopus (26) Google Scholar) looked at the trigonal crystal form of OmpF porin containing octyl-hydroxyethyl-sulfoxide (see Fig. 4in Penel et al.(37Penel S. Pebay Peyroula E. Rosenbusch J. Rummel G. Schirmer T. Timmins P.A. Biochimie (Paris). 1998; 80: 543-551Crossref PubMed Scopus (26) Google Scholar)), the detergent torus about each porin molecule had completely fused with its nearest neighbors to create a continuous detergent domain within the crystal. Clearly, detergents that should normally just produce small spherical or ellipsoidal micelles can be induced to form more complex structures at concentrations below 50% (w/w). Moreover, detergent-detergent interactions are often an integral part of the long range structure in membrane protein crystals. If detergent interactions and structure play a role in membrane protein crystal growth and integrity, could more lipid-like surfactants serve the same role? Landau and Rosenbusch proposed this question and came up with a novel way of crystallizing membrane proteins (40Landau E.M. Rosenbusch J.P. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 14532-14535Crossref PubMed Scopus (864) Google Scholar, 41Nollert P. Royant A. Pebay Peyroula E. Landau E.M. FEBS Lett. 1999; 457: 205-208Crossref PubMed Scopus (55) Google Scholar). In essence, a preformed surfactant phase with a more membrane-like structure might be used to partition membrane proteins into an environment that would favor close interactions suitable for nucleating and sustaining crystal growth. The bicontinuous cubic surfactant phases made by monoacyl glycerols (16Mitchell D.J. Tiddy G.J.T. Waring L. Bostock T. McDonald M.P. J. Chem. Soc. Faraday Trans. 1983; 79: 975-1000Crossref Google Scholar, 42Briggs J. Chung H. Caffrey M. J. Phys. II France. 1996; 6: 723-751Crossref Scopus (337) Google Scholar) seem ideal for this purpose as continuous regions of solvent and surfactant extend throughout the phase and can co-exist with a bulk solvent phase. Detergent-solubilized membrane protein, added externally, can easily partition into the bicontinuous cubic phase; the solvent channels allowed the manipulation of the aqueous environment to initiate crystallization. Although many of the assumptions made by Landau and Rosenbusch are not confirmed, their technique allowed the high resolution structure determination of bacteriorhodopsin (43Belrhali H. Nollert P. Royant A. Menzel C. Rosenbusch J.P. Landau E.M. Pebay Peyroula E. Structure. 1999; 7: 909-917Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar, 44Luecke H. Schobert B. Richter H.T. Cartailler J.P. Lanyi J.K. J. Mol. Biol. 1999; 291: 899-911Crossref PubMed Scopus (1301) Google Scholar) and halorhodopsin (45Kolbe M. Besir H. Essen L.O. Oesterhelt D. Science. 2000; 288: 1390-1396Crossref PubMed Scopus (478) Google Scholar). The crystal structure of bacteriorhodopsin obtained from the cubic phase system discussed above (43Belrhali H. Nollert P. Royant A. Menzel C. Rosenbusch J.P. Landau E.M. Pebay Peyroula E. Structure. 1999; 7: 909-917Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar, 44Luecke H. Schobert B. Richter H.T. Cartailler J.P. Lanyi J.K. J. Mol. Biol. 1999; 291: 899-911Crossref PubMed Scopus (1301) Google Scholar) showed a remarkable feature: a layer of lipid molecules was resolved on the protein surface. The nature of the lipids, originating from the native bacterial membrane, and their positioning in the grooves and crevices of the protein (Fig. 4) suggest specific and well defined protein-lipid interactions. Over the years, numerous studies have demonstrated that membrane lipids are rapidly exchanging at the surface of integral membrane proteins (46Horvath L.I. Brophy P.J. Marsh D. Biophys. J. 1993; 64: 622-631Abstract Full Text PDF PubMed Scopus (36) Google Scholar), even though a motionally restricted population was observed and quantified by EPR (47Marsh D. Horvath L.I. Biochim. Biophys. Acta. 1998; 1376: 267-296Crossref PubMed Scopus (223) Google Scholar). The functional significance of this “annular layer” of lipid has been much debated, but for many purposes the bilayer has been usefully considered as a hydrophobic solvent, albeit complex in its properties (48White S.H. Wimley W.C. Annu. Rev. Biophys. Biomol. Struct. 1999; 28: 319-365Crossref PubMed Scopus (1480) Google Scholar) (see also the first minireview in this series by Whiteet al. (64White S.H. Ladokhin A.S. Jayasinghe S. Hristova K. J. Biol. Chem. 2001; 276: 32395-32398Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar)). With the advent of high resolution crystal structures of membrane proteins, the observation of protein-bound lipid molecules now appears to be becoming a rule rather than an exception. Moreover, these crystalline complexes of membrane proteins and lipid do not contain just unusual lipids, such as cardiolipin (49McAuley K.E. Fyfe P.K. Ridge J.P. Isaacs N.W. Cogdell R.J. Jones M.R. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 14706-14711Crossref PubMed Scopus (207) Google Scholar) or diether lipids (44Luecke H. Schobert B. Richter H.T. Cartailler J.P. Lanyi J.K. J. Mol. Biol. 1999; 291: 899-911Crossref PubMed Scopus (1301) Google Scholar), but also more common phospholipids. The structure of bovine cytochrome c oxidase at 2.8-Å resolution revealed 5 phosphatidylethanolamine and 3 phosphatidylglycerol molecules per 200-kDa monomer (50Tsukihara T. Aoyama H. Yamashita E. Tomizaki T. Yamaguchi H. Shinzawa-Itoh K. Nakashima R. Yaono R. Yoshikawa S. Science. 1996; 272: 1136-1144Crossref PubMed Scopus (1921) Google Scholar). At higher resolution (2.0 Å), 14 phospholipids, including 5 cardiolipin molecules, have been identified, 2S. Yoshikawa, personal communication. which are still only a subset of the 56 lipids with restricted mobility that have been identified by EPR (47Marsh D. Horvath L.I. Biochim. Biophys. Acta. 1998; 1376: 267-296Crossref PubMed Scopus (223) Google Scholar). These recent crystallographic results imply that lipid may help membrane proteins assume more stable and homogeneous conformations. Hence, many detergents may work best along with retention of some native lipid (51Banerjee P. Joo J.B. Buse J.T. Dawson G. Chem. Phys. Lipids. 1995; 77: 65-78Crossref PubMed Scopus (95) Google Scholar). In contrast, complete lipid removal demands that a detergent must be able to substitute successfully for most, if not all, bound lipid (e.g. dodecyl phosphocholine used in NMR structure determination (52Arora A. Abildgaard F. Bushweller J.H. Tamm L.K. Nat. Struct. Biol. 2001; 8: 334-338Crossref PubMed Scopus (350) Google Scholar, 53MacKenzie K.R. Prestegard J.H. Engelman D.M. Science. 1997; 276: 131-133Crossref PubMed Scopus (872) Google Scholar)). Nonetheless, the maintenance of some lipid-protein interactions may be critical for procedures like crystallization. The crystal structures of rhodopsin (54Palczewski K. Kumasaka T. Hori T. Behnke C.A. Motoshima H. Fox B.A. Le Trong I. Teller D.C. Okada T. Stenkamp R.E. Yamamoto M. Miyano M. Science. 2000; 289: 739-745Crossref PubMed Scopus (5023) Google Scholar) and the sarcoplasmic Ca2+ pump (55Toyoshima C. Nakasako M. Nomura H. Ogawa H. Nature. 2000; 405: 647-655Crossref PubMed Scopus (1609) Google Scholar) emphasize this point. In the case of rhodopsin, minimal purification was used, including a single detergent extraction step (56Okada T. Le Trong I. Fox B.A. Behnke C.A. Stenkamp R.E. Palczewski K. J. Struct. Biol. 2000; 130: 73-80Crossref PubMed Scopus (153) Google Scholar), whereas the crystallization of the Ca2+ pump involved re-addition of lipid (55Toyoshima C. Nakasako M. Nomura H. Ogawa H. Nature. 2000; 405: 647-655Crossref PubMed Scopus (1609) Google Scholar). The significance of these findings is profound in terms of how we approach the use of detergents in purification. As mentioned earlier, the complete removal of lipid to obtain monodisperse, homogeneous PDCs was an early goal for x-ray crystallography or NMR to minimize self-association into insoluble, polydisperse aggregates (28Kragh-Hansen U. le Maire M. Moller J.V. Biophys. J. 1998; 75: 2932-2946Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar), which is often promoted by phospholipid. However, complete removal of bound lipid from many membrane proteins is rarely achieved and is often detrimental to structure and function (13Haneskog L. Andersson L. Brekkan E. Englund A.K. Kameyama K. Liljas L. Greijer E. Fischbarg J. Lundahl P. Biochim. Biophys. Acta. 1996; 1282: 39-47Crossref PubMed Scopus (20) Google Scholar, 57De Foresta B. Henao F. Champeil P. Eur. J. Biochem. 1994; 223: 359-369Crossref PubMed Scopus (25) Google Scholar, 58Lund S. Orlowski S. de Foresta B. Champeil P. le Maire M. Moller J.V. J. Biol. Chem. 1989; 264: 4907-4915Abstract Full Text PDF PubMed Google Scholar). Even when reasonably active forms can be maintained in detergent, the structural flexibility/integrity of membrane proteins may be influenced by the loss of associated lipid. For bacteriorhodopsin, NMR studies (59Tanio M. Tuzi S. Yamaguchi S. Konishi H. Naito A. Needleman R. Lanyi J.K. Saito H. Biochim. Biophys. Acta. 1998; 1375: 84-92Crossref PubMed Scopus (24) Google Scholar) clearly showed changes as native lipid was removed. Finally, conditions and detergents that can maintain native-like activity (60Mahapatro S.N. Robinson N.C. Biochemistry. 1990; 29: 764-770Crossref PubMed Scopus (37) Google Scholar, 61Thompson D.A. Ferguson-Miller S. Biochemistry. 1983; 22: 3178-3187Crossref PubMed Scopus (91) Google Scholar) may still induce subtle changes that are not detectable in routine assays (57De Foresta B. Henao F. Champeil P. Eur. J. Biochem. 1994; 223: 359-369Crossref PubMed Scopus (25) Google Scholar, 62Napiwotzki J. Shinzawa-Itoh K. Yoshikawa S. Kadenbach B. Biol. Chem. 1997; 378: 1013-1021Crossref PubMed Scopus (91) Google Scholar, 63Musatov A. Ortega-Lopez J. Robinson N.C. Biochemistry. 2000; 39: 12996-13004Crossref PubMed Scopus (58) Google Scholar). Hence, complete delipidation may not be the appropriate goal when designing purification procedures with the aim of structure determination (28Kragh-Hansen U. le Maire M. Moller J.V. Biophys. J. 1998; 75: 2932-2946Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar). The critical role of detergents in all aspects of membrane protein biochemistry cannot be fully addressed in the context of this short review. As noted above, the behavior of detergents clearly impacts membrane protein purification and crystallization, as well as reconstitution (1Rigaud J.L. Pitard B. Levy D. Biochim. Biophys. Acta. 1995; 1231: 223-246Crossref PubMed Scopus (398) Google Scholar), which was not discussed. However, a few generalities can be made that apply to all systems. The nature of the solubilization detergent is an important factor in determining the size and properties of the resulting PDCs. Moreover, the starting lipid content in the purified protein is a critical but often uncontrolled variable. Thus, we come to a new paradigm where “purer is not better” and isolation of specific protein-lipidcomplexes may be the more desirable goal for structural and functional studies of membrane proteins. Banerjee et al. (51Banerjee P. Joo J.B. Buse J.T. Dawson G. Chem. Phys. Lipids. 1995; 77: 65-78Crossref PubMed Scopus (95) Google Scholar) showed that different detergents extracted different kinds and amounts of lipids from the same membrane, along with protein, often with significant differences in activity of the isolated protein. Such careful studies may be de rigueur for the successful structural analysis of many membrane proteins." @default.
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