Peripheral membrane protein
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Peripheral membrane proteins are proteins that adhere only temporarily to the biological membrane with which they are associated. These molecules attach to integral membrane proteins, or penetrate the peripheral regions of the lipid bilayer. Therefore the so-called regulatory protein subunits of many ion channels and transmembrane receptors, for example, may be defined as peripheral membrane proteins. These proteins, in contrast to integral membrane proteins, tend to collect in the water-soluble fraction during protein purification. An exception to this rule are proteins with GPI anchors, whose purification properties may be similar to those of integral membrane proteins.
The boundary between peripheral and typical cytoplasmic proteins is blurred. Some proteins normally found in the cytoplasm (e.g. albumin, ribonuclease, lysozyme, or hemoglobin) can associate with lipid bilayers under certain experimental conditions in vitro. Some proteins associate strongly and even irreversibly with lipid bilayers if they are partially unfolded or form the molten globule state. Association of proteins with membranes can also be triggered by pH changes. Moreover, any positively charged protein will be attracted to a negatively charged membrane by nonspecific electrostatic interactions. Such interactions are strongly dependent on the ionic strength. Although relatively weak at the physiological ionic strength (0.1-0.2M KCl), the electrostatic interactions play an important role in membrane binding of many peripheral proteins, especially electron carriers (e.g. cytochrome c), and cationic toxins (e.g. charybdotoxin).
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[edit] Binding to the lipid bilayer
Orientations and penetration depths of many amphitropic proteins and peptides in the lipid bilayer were studied using site-directed spin labeling, chemical labeling, mutagenesis, fluorescence, solution and solid-state NMR spectroscopy, or other methods [1]. Membrane binding affinities have been determined by spectroscopic methods or calorimetry.
Typical amphitropic proteins associate with lipid bilayers through various hydrophobic anchors, such as amphiphilic α-helixes, exposed nonpolar loops, post-translationally acylated or lipidated amino acid residues, or acyl chains of specifically bound regulatory lipids such as inositol phosphates. The hydrophobic interactions are important even for highly cationic peptides and proteins of natural origin, such as the polybasic domain of MARCKS protein or histactophilin, when their natural hydrophobic anchors are present. Surprisingly, even unfolded peptides can penetrate deep across the lipid head group region and reach the hydrocarbon interior of membrane if these peptides have a few nonpolar residues <ref name="Ellena">Ellena, J.F., Moulthrop, J., Wu, J., Rauch, M., Jaysinghne, S., Castle, J.D., Cafiso, D.S. 2004. Membrane position of a basic aromatic peptide that sequesters phosphatidylinositol 4,5 bisphosphate determined by site-directed spin labeling and high-resolution NMR. Biophys. J. 87:3221-3233.</ref>. <ref name="Marcotte">Marcotte I., Dufourc E.J., Ouellet M., Auger M. 2003. Interaction of the neuropeptide met-enkephalin with zwitterionic and negatively charged bicelles as viewed by 31P and 2H solid-state NMR. Biophys. J. 85: 328-339.</ref> <ref name="Zhang">Zhang W., Crocker E., McLaughlin S., Smith S.O. 2003. Binding of peptides with basic and aromatic residues to bilayer membranes: phenylalanine in the myristoylated alanine-rich C kinase substrate effector domain penetrates into the hydrophobic core of the bilayer. J. Biol. Chem. 278: 21459-21466.</ref> Such behavior is also typical for amphiphilic α-helical peptides. <ref name="Darkes">Darkes M.J.M., Davies S.M.A., Bradshaw J.P. 1997. Interaction of tachykinins with phospholipid membranes: A neutron diffraction study. Physica B 241: 1144-1147.</ref> <ref name="Hristova">Hristova, K., Wimley, W.C., Mishra, V.K., Anantharamiah, G.M., Segrest, J.P., and White, S.H. 1999. An amphipathic α-helix at a membrane interface: A structural study using a novel X-ray diffraction method. J. Mol. Biol. 290: 99–117.</ref> Contribution of electrostatic interactions to the binding is relatively small (~3 to 4 kcal/mol) at the physiological ionic strength for small cationic proteins, such as cytochrome c, charybdotoxin or hisactophilin <ref name="Ben-Tal"> Ben-Tal, N., Honig, B., Miller, C., and McLaughlin, S. 1997. Electrostatic binding of proteins to membranes. Theoretical predictions and experimental results with charybdotoxin and phospholipid vesicles. Biophys. J. 73: 1717-1727.</ref> <ref name="Sankaram">Sankaram M.B. and Marsh D. Protein-lipid interactions with peripheral membrane proteins. In: Protein-lipid interactions (Ed. A. Watts), Elsevier, 1993, pp. 127-162.</ref> <ref name="Hanakam"> Hanakam, F., Gerisch, G., Lotz, S., Alt, T., and Seelig, A. 1996. Binding of hisactophilin I and II to lipid membranes is controlled by a pH-dependent myristoyl-histidine switch. Biochemistry. 35: 11036-11044. </ref>
It seems that water-soluble proteins either reach the hydrocarbon interior of membrane (which provides some gain in the hydrophobic interactions with membrane) or remain completely in the aqueous solution to avoid energetic penalties associated with perturbation of the lipid bilayer (and then interact with the lipid bilayer only electrostatically). Typical amphitropic proteins belong to the former type. These two types of protein-lipid association have different thermodynamic parameters of binding, as can be illustrated by cytochrome c and poly-lysine, respectively <ref name="Papah"> Papahadjopoulos D., Moscarello M., Eylar E.H, and Isac T. 1975. Effects of proteins on thermotropic phase transitions of phospholipid membranes. Biochim. Biophys. Acta 401: 317-335.</ref> <ref name="Seelig'> Seelig J. 2004. Thermodynamics of lipid-peptide interactions. Biochim. Biophys. Acta 1666: 40-50. </ref>.
Association of amphitropic proteins with lipid bilayers in vitro depends on various experimental conditions, primarily the specific lipid composition of the membrane. For example, the presence of negatively charged lipids can improve the binding of peripheral proteins to model membranes. This effect may be due to different reasons, including electrostatic attraction of a cationic protein to the negatively charged membrane surface, specific binding of anionic lipid ligands to the protein cavities, reduced lateral pressure, or increased hydration of the membrane interfacial region due to strong electrostatic repulsions between the negatively charged head groups of lipids.
[edit] Different categories of amphitropic proteins with known 3D structures
[edit] Enzymes
- Alpha/beta hydrolase superfamily (bacterial, fungal, gastric and pacnreatic lipases, palmitoyl protein thioesterases, cutinase, and cholinesterases) [2]
- Phospholipase A2 [3]
- FabD/lysophospholipase-like (including cytosolic phospholipase A2) [4]
- Cholesterol oxidases [5]
- Carotenoid oxygenase [6]
- Lipoxygenases [7]
- Alpha toxins [8]
- Phospholipase C [9]
- Sphingomyelinase C [10]
- Transglycosidases [11]
- Ferrochelatase [12]
- Myotubularin-related protein [13]
- Glycosyltransferase MurG [14]
- Dihydroorotate dehydrogenases and glycolate oxidase [15]
- Vitelline membrane outer protein-I [16]
[edit] Structural/regulatory domains
- Annexins [17]
- GLA-domains (from blood coagulation system) [18]
- Influenza virus matrix M1 protein [19]
- Hisactophilin-1 [20]
- Seminal plasma protein [21]
- Translocation ATPase SecA [22]
- Exocyst complex component Sec5 [23]
- Synapsin I [24]
- Synuclein [25]
- Epididymal secretory proteins and Rho GDP-dissociation inhibitors [26]
- Rab GDP dissociation inhibitor alpha [27]
- Phosducin [28]
- Spectrin and α-actinin-2 [29]
- Peroxin pex5 and vesicular transport protein sec17 [30]
[edit] Membrane-targeting domains (“lipid clamps”)
- C2 domains [31]
- C2 domains of blood coagulation factors [32]
- C1 domains [33]
- PX domains [34]
- FYVE domains [35]
- PH domains and disabled homolog 1 [36]
- ENTH, VHS and CALM domains [37]
- Tubby protein [38]
[edit] Water-soluble transporters of hydrophobic substances
- Glycolipid transfer proteins [39]
- Lipocalins including retinol-binding proteins and fatty acid-binding proteins [40]
- Polyisoprenoid-binding protein [41]
- Ganglioside GM2 activators [42]
- α-Tocopherol and phosphatidylinositol sec14p transfer proteins [43]
- Sterol carrier protein [44]
- Phosphatidylinositol transfer proteins and STAR domains [45]
- Oxysterol-binding protein [46]
[edit] Electron carriers
- Cytochrome c [47]
- Cupredoxins (see Copper proteins) [48]
- High potential iron protein (see iron-sulfur proteins) [49]
- Adrenodoxin reductase [50]
- Electron transfer flavoproteins [51]
[edit] Polypeptide ligands (hormones, inhibitors, toxins, antimicrobial peptides)
- α-Helical peptide hormones [52]
- Tachykinin peptides [53]
- Saposin B and NK-lysin [54]
- Heat-stable enterotoxin B [55]
- Conotoxins, spider toxins, insect toxins, albumin 1, and leginsulin [56]
- Scorpion venom toxins [57]
- Snake venom toxins [58]
- Neurotoxin III [59]
- Defensins and sea anemone sodium channel toxins [60]
- Poneratoxin and mastoparan [61]
- α-Conotoxins [62]
- Macrocyclic bacteriocins: subtilosin and microcin J25 [63]
- Tricyclic peptide RP71935 [64]
- Gramicidin S [65]
- Antimicrobial peptide HP [66]
- Lactoferricin B [67]
- Cyclic lipopeptide antibiotics: daptomycin and tsushimycin [68]
- Cyclotides [69]
- Leucocin-like bacteriocins [70]
[edit] Channel-forming proteins and peptides
- Apoptosis regulator Bcl-2 [71]
- Colicin A [72]
- δ-Endotoxins [73]
- Anemone pore-forming cytolysins [74]
- Perfringolysin [75]
- Botulinum neurotoxin B [76]
- Crambin, γ-purothionin, and hellethionin [77]
- Bacteriocin AS-48 [78]
- Ectatomin [79]
- Magainin [80]
- Peptaibols [81]
- Insect defensins [82]
- Plant defensins [83]
- Moricins [84]
- Pleruocidin [85]
- Lantibiotic peptides: Actagardine, mersacidin and nisin [86]
[edit] Footnotes
<references/>
[edit] General references
- Protein-lipid interactions (Ed. L.K. Tamm) Wiley, 2005.
- Cho, W. and Stahelin, R.V. 2005. Membrane-protein interactions in cell signaling and membrane trafficking. Annu. Rev. Biophys. Biomol. Struct. 34: 119–151.
- Goni F.M. 2002. Non-permanent proteins in membranes: when proteins come as visitors. Mol. Membr. Biol. 19: 237-245.
- Johnson J.E. and Cornell R.B. 1999. Amphitropic proteins: regulation by reversible membrane interactions. Mol. Membr. Biol. 16: 217-235.
- Seaton B.A. and Roberts M.F. Peripheral membrane proteins. pp. 355-403. In Biological Membranes (Eds. K. Mertz and B.Roux), Birkhauser Boston, 1996.
- Benga G. Protein-lipid interactions in biological membranes, pp.159-188. In Structure and Properties of Biological Membranes, vol. 1 (Ed. G. Benga) Boca Raton CRC Press, 1985.
- Kessel A. and Ben-Tal N. 2002. Free energy determinants of peptide association with lipid bilayers. In Current Topics in Membranes 52: 205-253.
- Malmberg N.J., and Falke J.J. 2005. Use of EPR power saturation to analyze the membrane-docking geometries of peripheral proteins: Applications to C2 domains. Ann. Rev. Biophys. Biomol. Struct. 34: 71-90.
- McIntosh T.J. and Simon S.A. 2006. Roles of bilayer material properties in function and distribution of membrane proteins. Annu. Rev. Biophys. Biomol. Struct. 35: 177-198.
[edit] See also
- Membrane proteins
- Lipoproteins
- Integral membrane proteins
- Transmembrane proteins
- Antimicrobial peptides
[edit] External links
- Orientations of Proteins in Membranes (OPM) database 3D structures of some peripheral proteins and their calculated orientations in membranes
- DOLOP Genomics-oriented database of bacterial lipoproteins
- Peptaibol database
- Antimicrobial Peptide Database
