Membrane protein

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Membrane protein complexes of photosynthesis in the thylakoid membrane Thylakoid membrane 3.svg
Membrane protein complexes of photosynthesis in the thylakoid membrane

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 and can either penetrate the membrane (transmembrane) or associate with one or the other side of a membrane (integral monotopic). Peripheral membrane proteins are transiently associated with the cell membrane.

Contents

Membrane proteins are common, and medically important—about a third of all human proteins are membrane proteins, and these are targets for more than half of all drugs. [1] Nonetheless, compared to other classes of proteins, determining membrane protein structures remains a challenge in large part due to the difficulty in establishing experimental conditions that can preserve the correct conformation of the protein in isolation from its native environment.

Function

Membrane proteins perform a variety of functions vital to the survival of organisms: [2]

The localization of proteins in membranes can be predicted reliably using hydrophobicity analyses of protein sequences, i.e. the localization of hydrophobic amino acid sequences.

Integral membrane proteins

Schematic representation of transmembrane proteins: 1. a single transmembrane a-helix (bitopic membrane protein) 2. a polytopic transmembrane a-helical protein 3. a polytopic transmembrane b-sheet protein
The membrane is represented in light-brown. Polytopic membrane protein.png
Schematic representation of transmembrane proteins: 1. a single transmembrane α-helix (bitopic membrane protein) 2. a polytopic transmembrane α-helical protein 3. a polytopic transmembrane β-sheet protein
The membrane is represented in light-brown.

Integral membrane proteins are permanently attached to the membrane. Such proteins can be separated from the biological membranes only using detergents, nonpolar solvents, or sometimes denaturing agents.[ citation needed ] They can be classified according to their relationship with the bilayer:

Peripheral membrane proteins

Schematic representation of the different types of interaction between monotopic membrane proteins and the cell membrane: 1. interaction by an amphipathic a-helix parallel to the membrane plane (in-plane membrane helix) 2. interaction by a hydrophobic loop 3. interaction by a covalently bound membrane lipid (lipidation) 4. electrostatic or ionic interactions with membrane lipids (e.g. through a calcium ion) Monotopic membrane protein.svg
Schematic representation of the different types of interaction between monotopic membrane proteins and the cell membrane: 1. interaction by an amphipathic α-helix parallel to the membrane plane (in-plane membrane helix) 2. interaction by a hydrophobic loop 3. interaction by a covalently bound membrane lipid ( lipidation ) 4. electrostatic or ionic interactions with membrane lipids (e.g. through a calcium ion)

Peripheral membrane proteins are temporarily attached either to the lipid bilayer or to integral proteins by a combination of hydrophobic, electrostatic, and other non-covalent interactions. Peripheral proteins dissociate following treatment with a polar reagent, such as a solution with an elevated pH or high salt concentrations.[ citation needed ]

Integral and peripheral proteins may be post-translationally modified, with added fatty acid, diacylglycerol [8] or prenyl chains, or GPI (glycosylphosphatidylinositol), which may be anchored in the lipid bilayer.

Polypeptide toxins

Polypeptide toxins and many antibacterial peptides, such as colicins or hemolysins, and certain proteins involved in apoptosis, are sometimes considered a separate category. These proteins are water-soluble but can aggregate and associate irreversibly with the lipid bilayer and become reversibly or irreversibly membrane-associated.[ citation needed ]

In genomes

Membrane proteins, like soluble globular proteins, fibrous proteins, and disordered proteins, are common. [9] It is estimated that 20–30% of all genes in most genomes encode for membrane proteins. [10] [11] For instance, about 1000 of the ~4200 proteins of E. coli are thought to be membrane proteins, 600 of which have been experimentally verified to be membrane resident. [12] In humans, current thinking suggests that fully 30% of the genome encodes membrane proteins. [13]

In disease

Membrane proteins are the targets of over 50% of all modern medicinal drugs. [1] Among the human diseases in which membrane proteins have been implicated are heart disease, Alzheimer's and cystic fibrosis. [13]

Purification of membrane proteins

Although membrane proteins play an important role in all organisms, their purification has historically, and continues to be, a huge challenge for protein scientists. In 2008, 150 unique structures of membrane proteins were available, [14] and by 2019 only 50 human membrane proteins had had their structures elucidated. [13] In contrast, approximately 25% of all proteins are membrane proteins. [15] Their hydrophobic surfaces make structural and especially functional characterization difficult. [13] [16] Detergents can be used to render membrane proteins water-soluble, but these can also alter protein structure and function. [13] Making membrane proteins water-soluble can also be achieved through engineering the protein sequence, replacing selected hydrophobic amino acids with hydrophilic ones, taking great care to maintain secondary structure while revising overall charge. [13]

Affinity chromatography is one of the best solutions for purification of membrane proteins. The activity of membrane proteins decreases very fast in contrast to other proteins.[ citation needed ] So, affinity chromatography provides a fast and specific purification of membrane proteins. The polyhistidine-tag is a commonly used tag for membrane protein purification, [17] and the alternative rho1D4 tag has also been successfully used. [18] [19]

See also

Related Research Articles

<span class="mw-page-title-main">Biological membrane</span> Enclosing or separating membrane in organisms acting as selective semi-permeable barrier

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 cell and another. Biological membranes, in the form of eukaryotic cell membranes, consist of a phospholipid bilayer with embedded, integral and peripheral proteins used in communication and transportation of chemicals and ions. The bulk of lipids in a cell membrane provides a fluid matrix for proteins to rotate and laterally diffuse for physiological functioning. Proteins are adapted to high membrane fluidity environment of the lipid bilayer with the presence of an annular lipid shell, consisting of lipid molecules bound tightly to the surface of integral membrane proteins. The cell membranes are different from the isolating tissues formed by layers of cells, such as mucous membranes, basement membranes, and serous membranes.

Protein targeting or protein sorting is the biological mechanism by which proteins are transported to their appropriate destinations within or outside the cell. Proteins can be targeted to the inner space of an organelle, different intracellular membranes, the plasma membrane, or to the exterior of the cell via secretion. Information contained in the protein itself directs this delivery process. Correct sorting is crucial for the cell; errors or dysfunction in sorting have been linked to multiple diseases.

A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs may consist of one or several alpha-helices or a transmembrane beta barrel. Because the interior of the lipid bilayer is hydrophobic, the amino acid residues in TMDs are often hydrophobic, although proteins such as membrane pumps and ion channels can contain polar residues. TMDs vary greatly in size and hydrophobicity; they may adopt organelle-specific properties.

<span class="mw-page-title-main">Integral membrane protein</span> Type of membrane protein that is permanently attached to the biological membrane

An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All transmembrane proteins can be classified as IMPs, but not all IMPs are transmembrane proteins. IMPs comprise a significant fraction of the proteins encoded in an organism's genome. Proteins that cross the membrane are surrounded by annular lipids, which are defined as lipids that are in direct contact with a membrane protein. Such proteins can only be separated from the membranes by using detergents, nonpolar solvents, or sometimes denaturing agents.

<span class="mw-page-title-main">Transmembrane protein</span> Protein spanning across a biological membrane

A transmembrane protein 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 frequently undergo significant conformational changes to move a substance through the membrane. They are usually highly hydrophobic and aggregate and precipitate in water. They require detergents or nonpolar solvents for extraction, although some of them (beta-barrels) can be also extracted using denaturing agents.

<span class="mw-page-title-main">Peripheral membrane protein</span> Membrane proteins that adhere temporarily to membranes with which they are associated

Peripheral membrane proteins, or extrinsic membrane proteins, are membrane proteins that adhere only temporarily to the biological membrane with which they are associated. These proteins attach to integral membrane proteins, or penetrate the peripheral regions of the lipid bilayer. The regulatory protein subunits of many ion channels and transmembrane receptors, 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 procedure. Proteins with GPI anchors are an exception to this rule and can have purification properties similar to those of integral membrane proteins.

<span class="mw-page-title-main">Membrane topology</span>

Topology of a transmembrane protein refers to locations of N- and C-termini of membrane-spanning polypeptide chain with respect to the inner or outer sides of the biological membrane occupied by the protein.

<span class="mw-page-title-main">Theories of general anaesthetic action</span> How drugs induce reversible suppression of consciousness

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<span class="mw-page-title-main">ATP-binding cassette transporter</span> Gene family

The ATP-binding cassette transporters are a transport system superfamily that is one of the largest and possibly one of the oldest gene families. It is represented in all extant phyla, from prokaryotes to humans. ABC transporters belong to translocases.

<span class="mw-page-title-main">Beta barrel</span>

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. Beta-strands in many beta-barrels are arranged in an antiparallel fashion. Beta barrel structures are named for resemblance to the barrels used to contain liquids. Most of them are water-soluble proteins and frequently bind hydrophobic ligands in the barrel center, as in lipocalins. Others span cell membranes and are commonly found in porins. Porin-like barrel structures are encoded by as many as 2–3% of the genes in Gram-negative bacteria. It has been shown that more than 600 proteins with various function contain the beta barrel structure.

<span class="mw-page-title-main">Aquaporin-1</span> Protein-coding gene in the species Homo sapiens

Aquaporin 1 (AQP-1) is a protein that in humans is encoded by the AQP1 gene.

<span class="mw-page-title-main">Flippase</span>

Flippases are transmembrane lipid transporter proteins located in the membrane which belong to ABC transporter or P4-type ATPase families. They are responsible for aiding the movement of phospholipid molecules between the two leaflets that compose a cell's membrane. This is necessary to continue their normal function of growth and mobility. The possibility of active maintenance of an asymmetric distribution of molecules in the phospholipid bilayer was predicted in the early 1970s by Mark Bretscher. Although phospholipids diffuse rapidly in the plane of the membrane, their polar head groups cannot pass easily through the hydrophobic center of the bilayer, limiting their diffusion in this dimension. Some flippases - often instead called scramblases - are energy-independent and bidirectional, causing reversible equilibration of phospholipid between the two sides of the membrane, whereas others are energy-dependent and unidirectional, using energy from ATP hydrolysis to pump the phospholipid in a preferred direction. Flippases are described as transporters that move lipids from the exoplasmic to the cytosolic face, while floppases transport in the reverse direction.

<span class="mw-page-title-main">Membrane lipid</span> Lipid molecules on cell membrane

Membrane lipids are a group of compounds which form the lipid bilayer of the cell membrane. The three major classes of membrane lipids are phospholipids, glycolipids, and cholesterol. Lipids are amphiphilic: they have one end that is soluble in water ('polar') and an ending that is soluble in fat ('nonpolar'). By forming a double layer with the polar ends pointing outwards and the nonpolar ends pointing inwards membrane lipids can form a 'lipid bilayer' which keeps the watery interior of the cell separate from the watery exterior. The arrangements of lipids and various proteins, acting as receptors and channel pores in the membrane, control the entry and exit of other molecules and ions as part of the cell's metabolism. In order to perform physiological functions, membrane proteins are facilitated to rotate and diffuse laterally in two dimensional expanse of lipid bilayer by the presence of a shell of lipids closely attached to protein surface, called annular lipid shell.

Orientations of Proteins in Membranes (OPM) database provides spatial positions of membrane protein structures with respect to the lipid bilayer. Positions of the proteins are calculated using an implicit solvation model of the lipid bilayer. The results of calculations were verified against experimental studies of spatial arrangement of transmembrane and peripheral proteins in membranes.

<span class="mw-page-title-main">Cell surface receptor</span> Class of ligand activated receptors localized in surface of plama cell membrane

Cell surface receptors are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving extracellular molecules. They are specialized integral membrane proteins that allow communication between the cell and the extracellular space. The extracellular molecules may be hormones, neurotransmitters, cytokines, growth factors, cell adhesion molecules, or nutrients; they react with the receptor to induce changes in the metabolism and activity of a cell. In the process of signal transduction, ligand binding affects a cascading chemical change through the cell membrane.

Membrane curvature is the geometrical measure or characterization of the curvature of membranes. The membranes can be naturally occurring or man-made (synthetic). An example of naturally occurring membrane is the lipid bilayer of cells, also known as cellular membranes. Synthetic membranes can be obtained by preparing aqueous solutions of certain lipids. The lipids will then "aggregate" and form various phases and structures. According to the conditions and the chemical structures of the lipid, different phases will be observed. For instance, the lipid POPC tends to form lamellar vesicles in solution, whereas smaller lipids, such as detergents, will form micelles if the CMC was reached. There are five commonly proposed mechanisms by which membrane curvature is created, maintained, or controlled: lipid composition, shaped transmembrane proteins, protein motif insertion/BAR domains, protein scaffolding, and cytoskeleton scaffolding.

<span class="mw-page-title-main">WALP peptide</span> Class of peptides used for studying lipid membranes

WALP peptides are a class of synthesized, membrane-spanning α-helices composed of tryptophan (W), alanine (A), and leucine (L) amino acids. They are designed to study properties of proteins in lipid membranes such as orientation, extent of insertion, and hydrophobic mismatch.

<span class="mw-page-title-main">Cell membrane</span> Biological membrane that separates the interior of a cell from its outside environment

The cell membrane is a biological membrane that separates and protects the interior of a cell from the outside environment. The cell membrane consists of a lipid bilayer, made up of two layers of phospholipids with cholesterols interspersed between them, maintaining appropriate membrane fluidity at various temperatures. The membrane also contains membrane proteins, including integral proteins that span the membrane and serve as membrane transporters, and peripheral proteins that loosely attach to the outer (peripheral) side of the cell membrane, acting as enzymes to facilitate interaction with the cell's environment. Glycolipids embedded in the outer lipid layer serve a similar purpose. The cell membrane controls the movement of substances in and out of a cell, being selectively permeable to ions and organic molecules. In addition, cell membranes are involved in a variety of cellular processes such as cell adhesion, ion conductivity, and cell signalling and serve as the attachment surface for several extracellular structures, including the cell wall and the carbohydrate layer called the glycocalyx, as well as the intracellular network of protein fibers called the cytoskeleton. In the field of synthetic biology, cell membranes can be artificially reassembled.

Stephen H. White is an American Biophysicist, academic, and author. He is a Professor Emeritus of Physiology and Biophysics at the University of California, Irvine.

The QTY Code is a design method to transform membrane proteins that are intrinsically insoluble in water into variants with water solubility, while retaining their structure and function.

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Further reading

Organizations

Membrane protein databases