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).

Contents 1 Binding to the lipid bilayer 2 Different categories of amphitropic proteins with known 3D structures 2.1 Enzymes 2.2 Structural domains 2.3 Membrane-targeting domains (“lipid clamps”) 2.4 Water-soluble transporters of hydrophobic substances 2.5 Electron carriers 2.6 Polypeptide ligands (hormones, inhibitors, toxins, antimicrobial peptides) 2.7 Channel-forming proteins and peptides 3 Footnotes 4 General references 5 See also 6 External links

[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 ^[1]. ^{[2] [3]} Such behavior is also typical for amphiphilic α-helical peptides. ^{[4] [5]} 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 ^{[6] [7] [8]}

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 ^{[9] [10]}.

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

These enzymes may participate in metabolism of different membrane components, such as lipids (phospholipases and cholesterol oxidases), cell wall oligosaccharides (glycosyltransferase and transglycosidases), or proteins (signal peptidase and palmitoyl protein thioesterases). They can also digest lipids that form micelles or nonpolar droplets in water (pancreatic lipases).

• 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 domains

Structural domains mediate attachment of other proteins to membranes. Their binding to membranes can be mediated by Ca2+ ions that form bridges between the acidic protein residues and phosphate groups of lipids, as in annexins or GLA domains.

• Annexins [17]
• GLA-domains of 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”)

Membrane-targeting domains associate specifically with head groups of their lipid ligands embedded into the membrane. For example, PX domains have binding pockets foe head groups of PS, PA and phosphoinositide (PI(3)P, PI(4,5)P2 and PI(3,4)P2) lipids, ENTH domains bind PI(4,5)P2 and PI(3,5)P2, whereas FYVE domains are more specific for PI(3)P. These lipid ligands are present in different concentrations in distinct types of biological membranes. Hence, each protein is targeted to its own membrane.

• C2 domains [31]
• Discoidin 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

These peripheral proteins function as carriers of non-polar compounds between different types of cell membranes or between membranes and cytosolic protein complexes. The transported substances are phosphatidylinositol, tocopherol, gangliosides, glycolipids, sterol derivatives, retinol, or fatty acids.

• 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 [48]
• High potential iron protein [49]
• Adrenodoxin reductase [50]
• Electron transfer flavoproteins [51]

[edit] Polypeptide ligands (hormones, inhibitors, toxins, antimicrobial peptides)

Different hormones, toxins, inhibitors, or antimicrobial peptides usually interact specifically with large TM protein complexes. They can be also accumulated at the lipid bilayer surface, prior to binding their protein targets. Such polypeptide ligands are often positively charged and interact electrostatically with anionic membranes.

• 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

Channel-forming polypeptides undergo oligomerization and significant conformational transitions and therefore can associate with membranes irreversibly. Structure of the membrane-bound channel has been determined only for α-hemolysin. In other cases, experimental structures represents a water-soluble conformation that weakly interacts with the lipid bilayer.

• 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

1. ^ 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.
2. ^ 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.
3. ^ 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.
4. ^ 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.
5. ^ 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.
6. ^ 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.
7. ^ 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.
8. ^ 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.
9. ^ 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.
10. ^ Seelig J. 2004. Thermodynamics of lipid-peptide interactions. Biochim. Biophys. Acta 1666: 40-50.

[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