A tetramer is a protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 with four subunits (tetrameric). There are homotetramer
A homotetramer is a protein complex made up of four identical subunits which are associated but not covalently bound. A heterotetramer is a 4-subunit complex where one or more subunits differ....

s (all subunit
Protein subunit
In structural biology, a protein subunit or subunit protein is a single protein molecule that assembles with other protein molecules to form a protein complex: a multimeric or oligomeric protein. Many naturally occurring proteins and enzymes are multimeric...

s are identical) such as glutathione S-transferase
Glutathione S-transferase
Enzymes of the glutathione S-transferase family are composed of many cytosolic, mitochondrial, and microsomal proteins. GSTs are present in eukaryotes and in prokaryotes, where they catalyze a variety of reactions and accept endogenous and xenobiotic substrates.GSTs can constitute up to 10% of...

 or single-strand binding protein
Single-strand binding protein
Single-strand binding protein, also known as SSB or SSBP, binds to single stranded regions of DNA to prevent premature annealing. The strands have a natural tendency to revert to the duplex form, but SSB binds to the single strands, keeping them separate and allowing the DNA replication machinery...

, dimers of hetero-dimers such as hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...

 (a dimer
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...

 of an alpha/beta dimer
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...

), and heterotetramer
A heterotetramer is protein containing four non-covalently bound subunits, wherein the subunits are not all identical. A homotetramer contains four identical subunits....

s, where each subunit is different.

Subunit interactions in tetramers

The interactions between subunits forming a tetramer is primarily determined by non covalent interaction. Hydrophobic effect
Hydrophobic effect
The hydrophobic effect is the observed tendency of nonpolar substances to aggregate in aqueous solution and exclude water molecules. The name, literally meaning "water-fearing," describes the segregation and apparent repulsion between water and nonpolar substances...

s, hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...

s and electrostatic interactions are the primary sources for this binding process between subunits. For homotetrameric proteins such as Sorbitol dehydrogenase
Sorbitol dehydrogenase
Sorbitol dehydrogenase is a protein. In humans this protein is encoded by the SORD gene.Sorbitol dehydrogenase is an enzyme in carbohydrate metabolism converting sorbitol, the sugar alcohol form of glucose, into fructose. Together with aldose reductase, it provides a way for the body to produce...

 (SDH), the structure is believed to have evolved going from a monomeric to a dimeric and finally a tetrameric structure in evolution. The binding process in SDH and many other tetrameric enzymes can be described by the gain in free energy
Gibbs free energy
In thermodynamics, the Gibbs free energy is a thermodynamic potential that measures the "useful" or process-initiating work obtainable from a thermodynamic system at a constant temperature and pressure...

 which can be determined from the rate of association and dissociation.
The following image shows the assembly of the four subunits (A,B,C and D) in SDH.

Hydrogen bonds between subunits

Hydrogen bonding networks between subunits has been shown to be important for the stability of the tetrameric quaternary protein structure. For example a study of SDH which used diverse methods such as protein sequence alignment
Sequence alignment
In bioinformatics, a sequence alignment is a way of arranging the sequences of DNA, RNA, or protein to identify regions of similarity that may be a consequence of functional, structural, or evolutionary relationships between the sequences. Aligned sequences of nucleotide or amino acid residues are...

s, structural comparisons, energy calculations, gel filtration experiments and enzyme kinetics experiments, could reveal an important hydrogen bonding network which stabilizes the tetrameric quaternary structure in mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...

ian SDH.

Tetramers in immunology

In immunology
Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...

, MHC tetramers can be used to quantify numbers of antigen-specific T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...

s (especially CD8+ T cells). MHC tetramers are based on recombinant class I molecules that, through the action of bacterial BirA, have been biotinylated. These molecules are folded with the peptide of interest and β2M and tetramerized by a fluorescently labeled streptavidin. (Streptavidin binds to four biotin
Biotin, also known as Vitamin H or Coenzyme R, is a water-soluble B-complex vitamin discovered by Bateman in 1916. It is composed of a ureido ring fused with a tetrahydrothiophene ring. A valeric acid substituent is attached to one of the carbon atoms of the tetrahydrothiophene ring...

s per molecule.) This tetramer reagent will specifically label T cells that express T cell receptors that are specific for a given peptide-MHC complex. For example, a Kb/FAPGNYPAL tetramer will specifically bind to Sendai virus specific cytotoxic T cell
Cytotoxic T cell
A cytotoxic T cell belongs to a sub-group of T lymphocytes that are capable of inducing the death of infected somatic or tumor cells; they kill cells that are infected with viruses , or are otherwise damaged or...

  in a C57BL/6 mouse. Antigen specific responses can be measured as CD8+, tetramer+ T cells as a fraction of all CD8+ lymphocytes.

The reason for using a tetramer, as opposed to a single labeled MHC class I molecule is that the tetrahedral tetramers can bind to three TCRs
T cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...

 at once, allowing specific binding in spite of the low (10-6 molar) affinity of the typical class I-peptide-TCR interaction.
MHC class II
MHC class II
MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells ....

tetramers can also be made although these are more difficult to work with practically.
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