Atetrameric protein is aprotein with aquaternary structure of four subunits (tetrameric).Homotetramers have four identicalsubunits (such asglutathione S-transferase), andheterotetramers arecomplexes of different subunits. A tetramer can be assembled asdimer of dimers with twohomodimer subunits (such assorbitol dehydrogenase), or twoheterodimer subunits (such ashemoglobin).
The interactions between subunits forming a tetramer is primarily determined by noncovalent interaction.[1]Hydrophobic effects,hydrogen bonds andelectrostatic interactions are the primary sources for this binding process between subunits. For homotetrameric proteins such assorbitol dehydrogenase (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 infree energy which can be determined from the rate of association and dissociation.[1] The above image shows the assembly of the four subunits (A,B,C and D) in SDH.
Hydrogen bonding networks between subunits has been shown to be important for the stability of the tetramericquaternary protein structure. For example, a study of SDH which used diverse methods such as proteinsequence alignments, structural comparisons, energy calculations, gel filtration experiments and enzyme kinetics experiments, could reveal an important hydrogen bonding network which stabilizes the tetrameric quaternary structure inmammalian SDH.[1]
Inimmunology, MHC tetramers can be used intetramer assays, to quantify numbers of antigen-specificT cells (especiallyCD8+ T cells). MHC tetramers are based on recombinantclass I molecules that, through the action of bacterial BirA, have beenbiotinylated. These molecules are folded with the peptide of interest andβ2M and tetramerized by a fluorescently labeledstreptavidin. (Streptavidin binds to fourbiotins 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 toSendai virus specificcytotoxic T cell in aC57BL/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 threeTCRs at once, allowing specific binding in spite of the low (1 micromolar) affinity of the typical class I-peptide-TCR interaction.MHC class II tetramers can also be made, although these are more difficult to work with practically.[2]
Ahomotetramer is a protein complex made up of four identical subunits which are associated but not covalently bound.[3] Conversely, aheterotetramer is a 4-subunit complex where one or more subunits differ.[4]
Examples of homotetramers include:
Examples of heterotetramers include haemoglobin (pictured), theNMDA receptor, someaquaporins,[7] someAMPA receptors, as well as someenzymes.[8]
Ion-exchange chromatography is useful for isolating specific heterotetrameric protein assemblies, allowing purification of specific complexes according to both the number and the position of charged peptide tags.[9][10]Nickel affinity chromatography may also be employed for heterotetramer purification.[11]
Multiple copies of a polypeptide encoded by agene often can form an aggregate referred to as a multimer. When a multimer is formed from polypeptides produced by two differentmutantalleles of a particular gene, the mixed multimer may exhibit greater functional activity than the unmixed multimers formed by each of the mutants alone. When a mixed multimer displays increased functionality relative to the unmixed multimers, the phenomenon is referred to asintragenic complementation. In humans,argininosuccinate lyase (ASL) is a homotetrameric enzyme that can undergo intragenic complementation. An ASL disorder in humans can arise from mutations in theASL gene, particularly mutations that affect the active site of the tetrameric enzyme. ASL disorder is associated with considerable clinical and genetic heterogeneity which is considered to reflect the extensive intragenic complementation occurring among different individual patients.[12][13][14]