Peripheral membrane proteins, or extrinsic membrane proteins, are
membrane protein
Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...
s that adhere only temporarily to the
biological membrane with which they are associated. These
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s attach to
integral membrane protein
An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All ''transmembrane proteins'' are IMPs, but not all IMPs are transmembrane proteins. IMPs comprise a sign ...
s, or penetrate the peripheral regions of the
lipid bilayer
The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...
. The regulatory protein subunits of many
ion channels and
transmembrane receptor
Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral me ...
s, for example, may be defined as peripheral membrane proteins. In contrast to integral membrane proteins, peripheral membrane proteins tend to collect in the water-soluble component, or fraction, of all the proteins extracted during a
protein purification Protein purification is a series of processes intended to isolate one or a few proteins from a complex mixture, usually cells, tissues or whole organisms. Protein purification is vital for the specification of the function, structure and interact ...
procedure. Proteins with
GPI anchors are an exception to this rule and can have purification properties similar to those of integral membrane proteins.
The reversible attachment of proteins to biological membranes has shown to regulate
cell signaling
In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...
and many other important cellular events, through a variety of mechanisms.
For example, the close association between many
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s and biological membranes may bring them into close proximity with their lipid
substrate(s).
Membrane binding may also promote rearrangement, dissociation, or
conformational changes within many protein structural domains, resulting in an activation of their
biological activity.
Additionally, the positioning of many proteins are localized to either the inner or outer surfaces or leaflets of their resident membrane.
This facilitates the assembly of multi-protein complexes by increasing the probability of any appropriate
protein–protein interactions.
Binding to the lipid bilayer
Peripheral membrane proteins may interact with other proteins or directly with the
lipid bilayer
The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...
. In the latter case, they are then known as ''amphitropic'' proteins.
Some proteins, such as
G-protein
G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their act ...
s and certain
protein kinase
A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a fu ...
s, interact with transmembrane proteins and the lipid bilayer simultaneously. Some polypeptide
hormones,
antimicrobial peptides, and
neurotoxins
Neurotoxins are toxins that are destructive to nerve tissue (causing neurotoxicity). Neurotoxins are an extensive class of exogenous chemical neurological insultsSpencer 2000 that can adversely affect function in both developing and mature nerv ...
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
The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...
that forms the cell surface membrane consists of a
hydrophobic
In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, t ...
inner core region sandwiched between two regions of
hydrophilic
A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press.
In contrast, hydrophobes are ...
ity, one at the inner surface and one at the outer surface of the cell membrane (see
lipid bilayer
The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...
article for a more detailed structural description of the cell membrane). The inner and outer surfaces, or interfacial regions, of model
phospholipid bilayers have been shown to have a thickness of around 8 to 10
Å, although this may be wider in
biological membranes that include large amounts of
ganglioside
A ganglioside is a molecule composed of a glycosphingolipid (ceramide and oligosaccharide) with one or more sialic acids (e.g. ''N''-acetylneuraminic acid, NANA) linked on the sugar chain. NeuNAc, an acetylated derivative of the carbohydrate si ...
s or
lipopolysaccharide
Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer ...
s.
The hydrophobic inner core region of typical
biological membranes
A biological membrane, biomembrane or cell membrane is a selectively permeable membrane that separates the interior of a cell from the external environment or creates intracellular compartments by serving as a boundary between one part of the c ...
may have a thickness of around 27 to 32 Å, as estimated by
Small angle X-ray scattering (SAXS)
Small-angle X-ray scattering (SAXS) is a small-angle scattering technique by which nanoscale density differences in a sample can be quantified. This means that it can determine nanoparticle size distributions, resolve the size and shape of (monodis ...
.
The boundary region between the hydrophobic inner core and the hydrophilic interfacial regions is very narrow, at around 3 Å, (see
lipid bilayer
The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...
article for a description of its component chemical groups). Moving outwards away from the hydrophobic core region and into the interfacial hydrophilic region, the effective concentration of water rapidly changes across this boundary layer, from nearly zero to a concentration of around 2
M.
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.
Some water-soluble proteins associate with lipid bilayers ''irreversibly'' and can form transmembrane alpha-helical or
beta-barrel
In protein structures, a beta barrel is a beta sheet composed of tandem repeats that twists and coils to form a closed toroidal structure in which the first strand is bonded to the last strand (hydrogen bond). Beta-strands in many beta-barrels are ...
channels. Such transformations occur in
pore forming toxins
Pore-forming proteins (PFTs, also known as pore-forming toxins) are usually produced by bacteria, and include a number of protein exotoxins but may also be produced by other organisms such as apple snails that produce perivitellin-2 or earthwo ...
such as
colicin
A colicin is a type of bacteriocin produced by and toxic to some strains of ''Escherichia coli''. Colicins are released into the environment to reduce competition from other bacterial strains. Colicins bind to outer membrane receptors, using them ...
A, alpha-hemolysin, and others. They may also occur in
BcL-2 like protein , in some amphiphilic
antimicrobial peptides , and in certain
annexin
Annexin is a common name for a group of cellular proteins. They are mostly found in eukaryotic organisms (animal, plant and fungi).
In humans, the annexins are found inside the cell. However some annexins (Annexin A1, Annexin A2, and Annexin A5) ...
s . These proteins are usually described as peripheral as one of their conformational states is water-soluble or only loosely associated with a membrane.
Membrane binding mechanisms
The association of a protein with a
lipid bilayer
The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...
may involve significant changes within
tertiary structure
Protein tertiary structure is the three dimensional shape of a protein. The tertiary structure will have a single polypeptide chain "backbone" with one or more protein secondary structures, the protein domains. Amino acid side chains may i ...
of a protein. These may include the
folding
Fold, folding or foldable may refer to:
Arts, entertainment, and media
* ''Fold'' (album), the debut release by Australian rock band Epicure
* Fold (poker), in the game of poker, to discard one's hand and forfeit interest in the current pot
*Abov ...
of regions of protein structure that were previously unfolded or a re-arrangement in the folding or a refolding of the membrane-associated part of the proteins. It also may involve the formation or dissociation of protein
quaternary structure
Protein quaternary structure is the fourth (and highest) classification level of protein structure. Protein quaternary structure refers to the structure of proteins which are themselves composed of two or more smaller protein chains (also refe ...
s or
oligomeric complexes, and specific binding of
ion
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...
s,
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 surface 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.
Non-specific hydrophobic association
Amphitropic proteins associate with lipid bilayers via various
hydrophobic
In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, t ...
anchor structures. Such as
amphiphilic
An amphiphile (from the Greek αμφις amphis, both, and φιλíα philia, love, friendship), or amphipath, is a chemical compound possessing both hydrophilic (''water-loving'', polar) and lipophilic (''fat-loving'') properties. Such a compo ...
α-helix
The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ...
es, 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.
Covalently bound lipid anchors
Lipid anchored proteins are covalently attached to different
fatty acid
In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
acyl
In chemistry, an acyl group is a moiety derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids. It contains a double-bonded oxygen atom and an alkyl group (). In organic chemistry, the acyl group (IUPAC ...
chains on the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
ic side of the
cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
via
palmitoylation
Palmitoylation is the covalent attachment of fatty acids, such as palmitic acid, to cysteine (''S''-palmitoylation) and less frequently to serine and threonine (''O''-palmitoylation) residues of proteins, which are typically membrane protein ...
,
myristoylation
Myristoylation is a lipidation modification where a myristoyl group, derived from myristic acid, is covalently attached by an amide bond to the alpha-amino group of an N-terminal glycine residue. Myristic acid is a 14-carbon saturated fatty ...
, or
prenylation
Prenylation (also known as isoprenylation or lipidation) is the addition of hydrophobic molecules to a protein or a biomolecule. It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes, similar to ...
. On the exoplasmic face of the cell membrane, lipid anchored proteins are covalently attached to the
lipids
Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...
glycosylphosphatidylinositol (GPI) and
cholesterol
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
.
Protein association with membranes through the use of
acyl
In chemistry, an acyl group is a moiety derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids. It contains a double-bonded oxygen atom and an alkyl group (). In organic chemistry, the acyl group (IUPAC ...
ated residues is a
reversible process, as the acyl chain can be buried in a protein's hydrophobic binding pocket after dissociation from the membrane. This process occurs within the beta-subunits of
G-protein
G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their act ...
s. Perhaps because of this additional need for structural flexibility, lipid anchors are usually bound to the highly flexible segments of proteins tertiary structure that are not well resolved by
protein crystallographic studies.
Specific protein–lipid binding
Some
cytosolic
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
proteins are recruited to different cellular membranes by recognizing certain types of lipid found within a given membrane.
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
lipid head groups of the lipids to which they bind. This is a typical
biochemical protein–
ligand
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elec ...
interaction, and is stabilized by the formation of intermolecular
hydrogen bonds,
van der Waals interactions, and
hydrophobic interactions between the protein and lipid
ligand
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elec ...
. Such complexes are also stabilized by the formation of ionic bridges between the
aspartate or
glutamate residues of the protein and lipid phosphates via intervening
calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...
ions (Ca
2+). Such ionic bridges can occur and are stable when ions (such as Ca
2+) are already bound to a protein in solution, prior to lipid binding. The formation of ionic bridges is seen in the protein–lipid interaction between both protein
C2 type domains and
annexin
Annexin is a common name for a group of cellular proteins. They are mostly found in eukaryotic organisms (animal, plant and fungi).
In humans, the annexins are found inside the cell. However some annexins (Annexin A1, Annexin A2, and Annexin A5) ...
s..
Protein–lipid electrostatic interactions
Any positively charged protein will be attracted to a negatively charged membrane by nonspecific
electrostatic
Electrostatics is a branch of physics that studies electric charges at rest ( static electricity).
Since classical times, it has been known that some materials, such as amber, attract lightweight particles after rubbing. The Greek word for amb ...
interactions. However, not all peripheral peptides and proteins are cationic, and only certain sides of
membrane
A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. ...
are negatively charged. These include the cytoplasmic side of
plasma membranes, the outer leaflet of
outer bacterial membranes and
mitochondrial membranes. Therefore,
electrostatic interactions
Electrostatics is a branch of physics that studies electric charges at Rest (physics), rest (static electricity).
Since classical antiquity, classical times, it has been known that some materials, such as amber, attract lightweight particles af ...
play an important role in
membrane targeting of
electron
The electron ( or ) is a subatomic particle with a negative one elementary electric charge. Electrons belong to the first generation of the lepton particle family,
and are generally thought to be elementary particles because they have no ...
carriers such as
cytochrome c, cationic toxins such as
charybdotoxin, and specific membrane-targeting domains such as some
PH domain
In chemistry, pH (), historically denoting "potential of hydrogen" (or "power of hydrogen"), is a scale used to specify the acidity or basicity of an aqueous solution. Acidic solutions (solutions with higher concentrations of ions) are ...
s,
C1 domain
C1 domain (also known as phorbol esters/diacylglycerol binding domain) binds an important secondary messenger diacylglycerol (DAG), as well as the analogous phorbol esters. Phorbol esters can directly stimulate protein kinase C, PKC.
Phorbol es ...
s, and
C2 domain
A C2 domain is a protein structural domain involved in targeting proteins to cell membranes. The typical version (PKC-C2) has a beta-sandwich composed of 8 β-strands that co-ordinates two or three calcium ions, which bind in a cavity formed by ...
s.
Electrostatic interactions are strongly dependent on the
ionic strength of the solution. These interactions are relatively weak at the physiological ionic strength (
0.14M NaCl): ~3 to 4 kcal/mol for small cationic proteins, such as
cytochrome c,
charybdotoxin or
hisactophilin.
Spatial position in membrane
Orientations and penetration depths of many amphitropic proteins and peptides in membranes are studied using
site-directed spin labeling Site-directed spin labeling (SDSL) is a technique for investigating the structure and local dynamics of proteins using electron spin resonance. The theory of SDSL is based on the specific reaction of spin labels with amino acids. A spin label's bui ...
,
chemical labeling, measurement of membrane binding affinities of protein
mutants
In biology, and especially in genetics, a mutant is an organism or a new genetic character arising or resulting from an instance of mutation, which is generally an alteration of the DNA sequence of the genome or chromosome of an organism. It ...
,
fluorescence
Fluorescence is the emission of light by a substance that has absorbed light or other electromagnetic radiation. It is a form of luminescence. In most cases, the emitted light has a longer wavelength, and therefore a lower photon energy, tha ...
spectroscopy,
solution or solid-state
NMR spectroscopy
Nuclear magnetic resonance spectroscopy, most commonly known as NMR spectroscopy or magnetic resonance spectroscopy (MRS), is a spectroscopic technique to observe local magnetic fields around atomic nuclei. The sample is placed in a magnetic fie ...
,
ATR
FTIR spectroscopy,
X-ray or neutron diffraction,
and computational methods.
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,
ribonuclease
Ribonuclease (commonly abbreviated RNase) is a type of nuclease that catalyzes the degradation of RNA into smaller components. Ribonucleases can be divided into endoribonucleases and exoribonucleases, and comprise several sub-classes within ...
and
poly-lysine interact with membranes in this mode. However, typical amphitropic proteins have various hydrophobic anchors that penetrate the interfacial region and reach the hydrocarbon interior of the membrane. Such proteins "deform" the lipid bilayer, decreasing the temperature of lipid fluid-gel transition.
The binding is usually a strongly exothermic reaction.
Association of amphiphilic α-helices with membranes occurs similarly.
Intrinsically unstructured or
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.
Categories
Enzymes
Peripheral enzymes participate in
metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...
of different membrane components, such as lipids (
phospholipase
A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. Acids trigger the release of bound calcium from cellular stores and the consequent increase in free cytosolic Ca2+, an essential step in ...
s and
cholesterol oxidases),
cell wall oligosaccharides
An oligosaccharide (/ˌɑlɪgoʊˈsækəˌɹaɪd/; from the Greek ὀλίγος ''olígos'', "a few", and σάκχαρ ''sácchar'', "sugar") is a saccharide polymer containing a small number (typically two to ten) of monosaccharides (simple suga ...
(
glycosyltransferase
Glycosyltransferases (GTFs, Gtfs) are enzymes (EC 2.4) that establish natural glycosidic linkages. They catalyze the transfer of saccharide moieties from an activated nucleotide sugar (also known as the "glycosyl donor") to a nucleophilic glyco ...
and
transglycosidases), or proteins (
signal peptidase
Signal peptidases are enzymes that convert secretory and some membrane proteins to their mature or pro forms by cleaving their signal peptides from their N-termini.
Signal peptidases were initially observed in endoplasmic reticulum (ER)-deri ...
and
palmitoyl protein thioesterase
Palmitoyl protein hydrolase/thioesterases is an enzyme (EC 3.1.2.22) that removes thioester-linked fatty acyl groups such as palmitate from modified cysteine residues in proteins or peptides during lysosomal degradation. It catalyzes the reac ...
s).
Lipases
Lipase ( ) is a family of enzymes that catalyzes the hydrolysis of fats. Some lipases display broad substrate scope including esters of cholesterol, phospholipids, and of lipid-soluble vitamins and sphingomyelinases; however, these are usually tr ...
can also digest lipids that form
micelle
A micelle () or micella () (plural micelles or micellae, respectively) is an aggregate (or supramolecular assembly) of surfactant amphipathic lipid molecules dispersed in a liquid, forming a colloidal suspension (also known as associated coll ...
s or nonpolar droplets in water.
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
endosome
Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane can ...
s,
PtdIns(3,5)P2 in late
endosome
Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane can ...
s, and
PtdIns4P in the
Golgi).
Hence, each domain is targeted to a specific membrane.
*
C1 domain
C1 domain (also known as phorbol esters/diacylglycerol binding domain) binds an important secondary messenger diacylglycerol (DAG), as well as the analogous phorbol esters. Phorbol esters can directly stimulate protein kinase C, PKC.
Phorbol es ...
bind
diglyceride, diacylglycerol and
phorbol esters.
*
C2 domain
A C2 domain is a protein structural domain involved in targeting proteins to cell membranes. The typical version (PKC-C2) has a beta-sandwich composed of 8 β-strands that co-ordinates two or three calcium ions, which bind in a cavity formed by ...
bind
phosphatidylserine
Phosphatidylserine (abbreviated Ptd-L-Ser or PS) is a phospholipid and is a component of the cell membrane. It plays a key role in cell cycle signaling, specifically in relation to apoptosis. It is a key pathway for viruses to enter cells via ap ...
,
phosphatidylcholine
Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a headgroup.
They are a major component of biological membranes and can be easily obtained from a variety of readily available sources, such as egg yolk or soybea ...
or
PtdIns(3,4)P2 or
PtdIns(4,5)P2
Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)''P''2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)''P''2 is enriched at the plasma membrane where it is a substrate for a number of ...
.
*
Pleckstrin homology domain
Pleckstrin homology domain (PH domain) or (PHIP) is a protein domain of approximately 120 amino acids that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton.
This domain can bind phospha ...
PX domain and
Tubby protein, Tubby domainsbr>
bind different
Phosphatidylinositol, phosphoinositides
*
FYVE domainare more specific for PtdIns3P.
*
ENTH domain
The epsin N-terminal homology (ENTH) domain is a structural domain that is found in proteins involved in endocytosis and cytoskeletal machinery.
Structure
This domain is approximately 150 amino acids in length and is always found located at th ...
bind
PtdIns(3,4)P2 or
PtdIns(4,5)P2
Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)''P''2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)''P''2 is enriched at the plasma membrane where it is a substrate for a number of ...
.
*
ANTH
''Anth'' is a 1994 Indian action film directed by Sanjay Khanna, produced by Ashok Honda and starred Sunil Shetty, Somy Ali in pivotal roles. Aloknath, Paresh Rawal, Mohan Joshi, Deepak Shirke, Vijayendra Ghatge, Neena Gupta, Makrand Deshpand ...
domai
binds PtdIns(4,5)P2.
*Proteins from
Merlin (protein), ERM (ezrin/radixin/moesin) familybr>
bind PtdIns(4,5)P2.
*Other
Phosphatidylinositol, phosphoinositide-binding proteins include
phosphotyrosine-binding domai
and certain
PDZ domain
The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, viruses and animals. Proteins containing PDZ domains play a key role in anchoring receptor proteins in the membrane to ...
s. They bind PtdIns(4,5)P2.
*Discoidin domains of blood
coagulation
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanis ...
factor
*
ENTH, VHS and
ANTH
''Anth'' is a 1994 Indian action film directed by Sanjay Khanna, produced by Ashok Honda and starred Sunil Shetty, Somy Ali in pivotal roles. Aloknath, Paresh Rawal, Mohan Joshi, Deepak Shirke, Vijayendra Ghatge, Neena Gupta, Makrand Deshpand ...
domain
Structural domains
Structural domains mediate attachment of other proteins to membranes. Their binding to membranes can be mediated by
calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...
ions (Ca
2+) that form bridges between the acidic protein residues and phosphate groups of lipids, as in annexins or GLA domains.
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, fatty acids, water, macromolecules, red blood cells, phospholipids, and nucleotides.
*
Glycolipid transfer proteins
*
Lipocalin
The lipocalins are a family of proteins which transport small hydrophobic molecules such as steroids, bilins, retinoids, and lipids and most lipocalins are also able to bind to complexed iron (via siderophores or flavonoids) as well as heme. They ...
s including
retinol binding proteins and
fatty acid
In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
-binding proteins
*Polyisoprenoid-binding protein, such as
YceI protein domain
*
Ganglioside GM2 activator protein
GM2 ganglioside activator also known as GM2A is a protein which in humans is encoded by the ''GM2A'' gene.
Function
The protein encoded by this gene is a small glycolipid transport protein which acts as a substrate specific co-factor for the ...
s
*
CRAL-TRIO domain
CRAL-TRIO domain is a protein structural domain that binds small lipophilic molecules. This domain is named after Retinaldehyde-binding protein 1, cellular retinaldehyde-binding protein (CRALBP) and TRIO (gene), TRIO guanine exchange factor.
CRA ...
(α-
Tocopherol
Tocopherols (; TCP) are a class of organic chemical compounds (more precisely, various methylated phenols), many of which have vitamin E activity. Because the vitamin activity was first identified in 1936 from a dietary fertility factor in rat ...
and
phosphatidylinositol
Phosphatidylinositol (or Inositol Phospholipid) consists of a family of lipids as illustrated on the right, where red is x, blue is y, and black is z, in the context of independent variation, a class of the phosphatidylglycerides. In such molecul ...
sec14p transfer proteins)
*
Sterol carrier proteins
*
Phosphatidylinositol transfer proteins and STAR domains
*
Oxysterol-binding protein
Electron carriers
These proteins are involved in
electron transport chains. They include
cytochrome c,
cupredoxins,
high potential iron protein, adrenodoxin reductase, some
flavoprotein
Flavoproteins are proteins that contain a nucleic acid derivative of riboflavin.
Flavoproteins are involved in a wide array of biological processes, including removal of radicals contributing to oxidative stress, photosynthesis, and DNA repair. T ...
s, and others.
Polypeptide hormones, toxins, and antimicrobial peptides
Many hormones,
toxins,
inhibitors, or
antimicrobial peptides interact specifically with
transmembrane protein
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequent ...
complexes. They can also accumulate at the lipid bilayer surface, prior to binding their protein targets. Such polypeptide ligands are often positively charged and interact
electrostatically
Electrostatics is a branch of physics that studies electric charges at rest (static electricity).
Since classical times, it has been known that some materials, such as amber, attract lightweight particles after rubbing. The Greek word for amber ...
with
anionic
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conven ...
membranes.
Some water-soluble proteins and peptides can also form
transmembrane channels. They usually undergo
oligomerization, significant
conformational changes, and associate with membranes irreversibly. 3D structure of one such transmembrane channel,
α-hemolysin, has been determined. In other cases, the experimental structure represents a water-soluble conformation that interacts with the lipid bilayer peripherally, although some of the channel-forming peptides are rather hydrophobic and therefore were studied by
NMR spectroscopy
Nuclear magnetic resonance spectroscopy, most commonly known as NMR spectroscopy or magnetic resonance spectroscopy (MRS), is a spectroscopic technique to observe local magnetic fields around atomic nuclei. The sample is placed in a magnetic fie ...
in organic solvents or in the presence of
micelles
A micelle () or micella () (plural micelles or micellae, respectively) is an aggregate (or supramolecular assembly) of surfactant amphipathic lipid molecules dispersed in a liquid, forming a colloidal suspension (also known as associated coll ...
.
See also
*
Antimicrobial peptide
Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for a ...
s
*
Lipoprotein
A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, su ...
s
*
Membrane protein
Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...
s
*
Transmembrane proteins
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
References
General references
*
*
*
*
*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.
*
*
External links
Peripheral membrane proteinsin
OPM database
Orientations of Proteins in Membranes (OPM) database provides spatial positions of membrane protein protein structure, structures with respect to the lipid bilayer. Positions of the proteins are calculated using an Implicit solvation, implicit sol ...
DOLOPGenomics-oriented database of bacterial lipoproteins
Peptaibol databaseAntimicrobial Peptide Database
{{Cell membranes
Peripheral membrane proteins