Peripheral membrane protein

Binding of peripheral proteins to the lipid bilayer

  Peripheral membrane proteins may interact with other proteins or directly with the lipid bilayer. In the latter case, they are then known as amphitropic proteins.^[3] Some proteins, such as neurotoxins accumulate at the membrane surface prior to locating and interacting with their cell surface receptor targets, which may themselves be peripheral membrane proteins.

The Phospholipid bilayer that forms the cell surface membrane consists of a lipopolysaccharides.^[6] The hydrophobic inner core region of typical Small angle X-ray scattering (SAXS).^[7] The boundary region between the hydrophobic inner core and the hydrophilic interfacial regions is very narrow, at around 3Å, (see M.^[8][9] The phosphate groups within phospholipid bilayers are fully hydrated or saturated with water and are situated around 5 Å outside the boundary of the hydrophobic core region (see Figures ).^[10]

Some water-soluble proteins associate with lipid bilayers irreversibly and can form transmembrane alpha-helical or antimicrobial peptides , and in certain annexins . These proteins are usually described as peripheral as one of their conformational states is water-soluble or only loosely associated with a membrane.^[11]

Membrane binding mechanisms

  The association of a protein with a ligands, or regulatory lipids.

Typical amphitropic proteins must interact strongly with the lipid bilayer in order to perform their biological functions. These include the enzymatic processing of lipids and other hydrophobic substances, membrane anchoring, and the binding and transfer of small nonpolar compounds between different cellular membranes. These proteins may be anchored to the bilayer as a result of hydrophobic interactions between the bilayer and exposed nonpolar residues at the suface of a protein, by specific non-covalent binding interactions with regulatory lipids , or through their attachment to covalently-bound lipid anchors.

It has been shown that the membrane binding affinities of many peripheral proteins depend on the specific lipid composition of the membrane with which they are associated.^[12]

Non-specific hydrophobic association

Amphitropic proteins associate with lipid bilayers via various α-helixes, exposed nonpolar loops, post-translationally acylated or lipidated amino acid residues, or acyl chains of specifically bound regulatory lipids such as phosphatidylinositol phosphates. Hydrophobic interactions have been shown to be important even for highly cationic peptides and proteins, such as the polybasic domain of the MARCKS protein or histactophilin, when their natural hydrophobic anchors are present. ^[13]

Covalently bound lipid anchors

Lipid anchored proteins are covalently attached to different protein crystalographic studies.

Specific protein-lipid binding

  Some cytosolic proteins are recruited to different cellular membranes by recognizing certain types of lipid found within a given membrane.^[16] Binding of a protein to a specific lipid occurs via specific membrane-targeting structural domains that occur within the protein and have specific binding pockets for the C2 type domains and annexins.

Protein-lipid electrostatic interactions

Any positively charged protein will be attracted to a negatively charged membrane by nonspecific electrostatic interactions. However, not all peripheral peptides and proteins are cationic, and only certain sides of C2 domains.

Electrostatic interactions are strongly dependent on the charybdotoxin or hisactophilin.^[17][18][13]

Spatial position in membrane

Orientations and penetration depths of many amphitropic proteins and peptides in membranes are studied using site-directed spin labeling,^[19] chemical labeling, measurement of membrane binding affinities of protein NMR spectroscopy,^[22] ATR FTIR spectroscopy,^[23] X-ray or neutron diffraction,^[24] and computational methods.^{[25][26][27][28]}

Two distinct membrane-association modes of proteins have been identified. Typical water-soluble proteins have no exposed nonpolar residues or any other hydrophobic anchors. Therefore, they remain completely in aqueous solution and do not penetrate into the lipid bilayer, which would be energetically costly. Such proteins interact with bilayers only electrostatically, for example, unfolded peptides with nonpolar residues or lipid anchors can also penetrate the interfacial region of the membrane and reach the hydrocarbon core, especially when such peptides are cationic and interact with negatively charged membranes.^[32][33][34]

Categories of peripheral proteins

Enzymes

Peripheral enzymes participate in micelles or nonpolar droplets in water.

Class	Function	Physiology	Structure
cholinesterases	[1]
Phospholipase A2 (secretory and cytosolic)	Hydrolysis of sn-2 lipid signaling.	[2] [3]
Lipid signaling	[4]
Cholesterol oxidases	Oxidizes and isomerizes cholesterol to cholest-4-en-3-one.[38]	Depletes cellular membranes of cholesterol, used in bacterial pathogenesis.	[5]
pigments, flavors, floral scents and defense compounds.	[6]
leukotrienes.	[7]
Alpha toxins	Cleave phospholipids in the cell membrane, similar to Phospholipase C.[41]	Bacterial pathogenesis, particularly by Clostridium perfringens.	[8]
phosphodiesterase, cleaves phosphodiester bonds.[42]	Processing of lipids such as sphingomyelin.	[9]
polysaccharides (glycoconjugates), MurG is involved in bacterial peptidoglycan biosynthesis.	[10] [11]
Ferrochelatase	Converts protoporphyrin IX into porphyrin metabolism, protoporphyrins are used to strengthen egg shells.	[12]
Myotubularin-related protein family	Lipid phosphatase that dephosphorylates PtdIns3P and PtdIns(3,5)P2.[45]	Required for muscle cell differentiation.	[13]
Dihydroorotate dehydrogenases	nucleotides in prokaryotic and eukaryotic cells.	[14]
Glycolate oxidase	Catalyses the hydroxy acids to the corresponding α-ketoacids.[47]	In green plants, the enzyme participates in photorespiration. In animals, the enzyme participates in production of oxalate.	[15]

Membrane-targeting domains (“lipid clamps”)

  Membrane-targeting domains associate specifically with head groups of their lipid ligands embedded into the membrane. These lipid ligands are present in different concentrations in distinct types of biological membranes (for example, PtdIns3P can be found mostly in membranes of early endosomes, PtdIns(3,5)P2 in late endosomes, and PtdIns4P in the Golgi).^[16] Hence, each domain is targeted to a specific membrane.

• phorbol esters.
• C2 domains [17] bind phosphatidylserine or phosphatidylcholine
• Pleckstrin homology domains [18], PX domains [19], and Tubby domains [20] bind different phosphoinositides
• FYVE domains [21] are more specific for PtdIns3P.
• ENTH domains [22] bind PtdIns(3,4)P2 or PtdIns(4,5)P2.
• ANTH domain [23] binds PtdIns(4,5)P2.
• Proteins from ERM (ezrin/radixin/moesin) family [24] bind PtdIns(4,5)P2.

• Other phosphoinositide-binding proteins include PDZ domains. They bind PtdIns(4,5)P2.
• Discoidin domains of blood coagulation factors [26]
• ANTH domains [27]

Structural domains

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

Class	Function	Physiology	Structure
Annexins	ion channel formation.	[28]
neurotransmitter release.	[29]
Synuclein	Unknown cellular function.[50]	Thought to play a role in regulating the stability and/or turnover of the plasma membrane. Associated with both Parkinson's disease and Alzheimer's disease.	[30]
GLA-domains of the blood coagulation cascade.	[31]
Spectrin and α-actinin-2	Found in several cytoskeletal and microfilament proteins.[52]	Maintenance of plasma membrane integrity and cytoskeletal structure.	[32]

Transporters of small hydrophobic molecules

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 [33]
• fatty acid-binding proteins [34]
• Polyisoprenoid-binding protein [35]
• Ganglioside GM2 activator proteins [36]
• CRAL-TRIO domain (α-Tocopherol and phosphatidylinositol sec14p transfer proteins) [37]
• Sterol carrier proteins [38]
• Phosphatidylinositol transfer proteins and STAR domains [39]
• Oxysterol-binding protein [40]

Electron carriers

These proteins are involved in high potential iron protein, adrenodoxin reductase, some flavoproteins, and others.

Polypeptide hormones, toxins, and antimicrobial peptides

Many electrostatically with anionic membranes.

Some water-soluble proteins and peptides can also form micelles.

Class	Proteins	Physiology
Venom toxins	Scorpion venom[41] Snake venom[42] Conotoxins[43] Poneratoxin (insect)[44]	Well known types of biotoxins include neurotoxins, cytotoxins, hemotoxins and necrotoxins. Biotoxins have two primary functions: predation (snake, scorpion and cone snail toxins) and defense (honeybee and ant toxins).[53]
Sea anemone toxins	Sea anemone sodium channel inhibitory toxin [45] Neurotoxin III [46] Cytolysins [47]	Inhibition of sodium and chemical warfare agents.[54]
Bacterial toxins	Perfringolysin O[48] Botulinum toxin B [49] Heat-stable enterotoxin B[50] δ-Endotoxins [51] microcin) Lantibiotic peptides [53] (see nisin) Gramicidin S [54]	neurotransmitter release.[55]
Fungal Toxins	Cyclic lipopeptide antibiotics daptomycin[55] Peptaibols [56]	These peptides are characterized by the presence of an unusual amino acid, α-aminoisobutyric acid, and exhibit antifungal properties due to their membrane channel-forming activities.[56]
Antimicrobial peptides	HP peptide[57] Saposin B and NK-lysin [58] Lactoferricin B [59] Magainin [60], Moricins [61], and Pleurocidin [62]	The modes of action by which antimicrobial peptides kill bacteria is varied and includes disrupting membranes, interfering with bacteriostatic.
Defensins	Insect defensins[63] Plant defensins[64]: Cyclotides [65] and thionins [66]	Defensins are a type of antimicrobial peptide; and are an important component of virtually all innate host defenses against microbial invasion. Defensins penetrate microbial cell membranes by way of electrical attraction, and form a pore in the membrane allowing efflux, which ultimately leads to the lysis of microorganisms.[57]
Neuronal peptides	Tachykinin peptides[67]	These proteins excite neurons, evoke behavioral responses, are potent vasodilatators, and are responsible for contraction in many types of smooth muscle.[58]
Apoptosis regulators	Bcl-2 [68]	Members of the Bcl-2 family govern mitochondrial outer membrane permeability. Bcl-2 itself suppresses apoptosis in a variety of cell types including lymphocytes and neuronal cells.

See also

• Membrane proteins
• Lipoproteins
• Transmembrane proteins
• Antimicrobial peptides

References

General references