Editing Cooperative binding (section)

== Examples ==
The list of molecular assemblies that exhibit cooperative binding of ligands is very large, but some examples are particularly notable for their historical interest, their unusual properties, or their physiological importance.

[[File:HemoglobinConformations.png|thumb|right|Cartoon representation of the protein hemoglobin in its two conformations: "tensed (T)" on the left corresponding to the deoxy form (derived from  [[Protein Data Bank|PDB]] id:11LFL) and "relaxed (R)" on the right corresponding to the oxy form (derived from  [[Protein Data Bank|PDB]] id:1LFT).]] As described in the historical section, the most famous example of cooperative binding is [[hemoglobin]]. Its quaternary structure, solved by [[Max Perutz]] using X-ray diffraction,<ref name=Perutz1960>{{cite journal | vauthors = Perutz MF, Rossmann MG, Cullis AF, Muirhead H, Will G, North AC | title = Structure of haemoglobin: a three-dimensional Fourier synthesis at 5.5-A. resolution, obtained by X-ray analysis | journal = Nature | volume = 185 | issue = 4711 | pages = 416–22 | date = February 1960 | pmid = 18990801 | doi = 10.1038/185416a0 | bibcode = 1960Natur.185..416P | s2cid = 4208282 }}</ref> exhibits a pseudo-symmetrical tetrahedron carrying four binding sites (hemes) for oxygen. Many other molecular assemblies exhibiting cooperative binding have been studied in great detail.

=== Multimeric enzymes ===
The activity of many [[enzyme]]s is  [[Allosteric regulation|regulated]] by allosteric effectors. Some of these enzymes are multimeric and carry several binding sites for the regulators.

[[Threonine ammonia-lyase|Threonine deaminase]] was one of the first enzymes suggested to behave like hemoglobin<ref name=Changeux1961>{{cite journal | vauthors = Changeux JP | title = The feedback control mechanisms of biosynthetic L-threonine deaminase by L-isoleucine | journal = Cold Spring Harbor Symposia on Quantitative Biology | volume = 26 | pages = 313–8 | year = 1961 | pmid = 13878122 | doi = 10.1101/SQB.1961.026.01.037 }}</ref> and shown to bind ligands cooperatively.<ref name=Changeux963>{{cite journal | last1 = Changeux | first1 = J.-P. | year = 1963 | title = 'Allosteric Interactions on Biosynthetic L-threonine Deaminase from E. coli K12 | journal = Cold Spring Harb Symp Quant Biol | volume = 28 | pages = 497–504 | doi=10.1101/sqb.1963.028.01.066}}</ref> It was later shown to be a tetrameric protein.<ref name=Gallagher1998>{{cite journal | vauthors = Gallagher DT, Gilliland GL, Xiao G, Zondlo J, Fisher KE, Chinchilla D, Eisenstein E | title = Structure and control of pyridoxal phosphate dependent allosteric threonine deaminase | journal = Structure | volume = 6 | issue = 4 | pages = 465–75 | date = April 1998 | pmid = 9562556 | doi = 10.1016/s0969-2126(98)00048-3 | doi-access = free }}</ref>

Another enzyme that has been suggested early to bind ligands cooperatively is [[aspartate transcarbamoylase|aspartate trans-carbamylase]].<ref name=Gerhart1962>{{cite journal | vauthors = Gerhart JC, Pardee AB | title = The enzymology of control by feedback inhibition | journal = The Journal of Biological Chemistry | volume = 237 | pages = 891–6 | date = March 1962 | issue = 3 | doi = 10.1016/S0021-9258(18)60389-8 | pmid = 13897943 | doi-access = free }}</ref> Although initial models were consistent with four binding sites,<ref name="Changeux1968">{{cite journal | vauthors = Changeux JP, Rubin MM | title = Allosteric interactions in aspartate transcarbamylase. 3. Interpretation of experimental data in terms of the model of Monod, Wyman, and Changeux | journal = Biochemistry | volume = 7 | issue = 2 | pages = 553–61 | date = February 1968 | pmid = 4868541 | doi = 10.1021/bi00842a601 }}</ref> its structure was later shown to be hexameric by [[William Lipscomb]] and colleagues.<ref name=Honzatko1982>{{cite journal | vauthors = Honzatko RB, Crawford JL, Monaco HL, Ladner JE, Ewards BF, Evans DR, Warren SG, Wiley DC, Ladner RC, Lipscomb WN | title = Crystal and molecular structures of native and CTP-liganded aspartate carbamoyltransferase from Escherichia coli | journal = Journal of Molecular Biology | volume = 160 | issue = 2 | pages = 219–63 | date = September 1982 | pmid = 6757446 | doi = 10.1016/0022-2836(82)90175-9 }}</ref>

=== Ion channels ===
Most [[ion channel]]s are formed of several identical or pseudo-identical monomers or domains, arranged symmetrically in biological membranes. Several classes of such channels whose opening is regulated by ligands exhibit cooperative binding of these ligands.

It was suggested as early as 1967<ref name=Karlin1967>{{cite journal | vauthors = Karlin A | title = On the application of "a plausible model" of allosteric proteins to the receptor for acetylcholine | journal = Journal of Theoretical Biology | volume = 16 | issue = 2 | pages = 306–20 | date = August 1967 | pmid = 6048545 | doi = 10.1016/0022-5193(67)90011-2 | bibcode = 1967JThBi..16..306K }}</ref> (when the exact nature of those channels was still unknown) that the [[nicotinic receptors|nicotinic acetylcholine receptors]] bound [[acetylcholine]] in a cooperative manner due to the existence of several binding sites. The purification of the receptor<ref name=changeux1970 >{{cite journal | vauthors = Changeux JP, Kasai M, Lee CY | title = Use of a snake venom toxin to characterize the cholinergic receptor protein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 67 | issue = 3 | pages = 1241–7 | date = November 1970 | pmid = 5274453 | pmc = 283343 | doi = 10.1073/pnas.67.3.1241 | bibcode = 1970PNAS...67.1241C | doi-access = free }}</ref> and its characterization demonstrated a pentameric structure with binding sites located at the interfaces between subunits, confirmed by the structure of the receptor binding domain.<ref name=Brejc2002>{{cite journal | vauthors = Brejc K, van Dijk WJ, Klaassen RV, Schuurmans M, van Der Oost J, Smit AB, Sixma TK | title = Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors | journal = Nature | volume = 411 | issue = 6835 | pages = 269–76 | date = May 2001 | pmid = 11357122 | doi = 10.1038/35077011 | bibcode = 2001Natur.411..269B | s2cid = 4415937 }}</ref>

[[IP3 receptor|Inositol triphosphate (IP3) receptors]] form another class of ligand-gated ion channels exhibiting cooperative binding.<ref name=Meyer1988>{{cite journal | vauthors = Meyer T, Holowka D, Stryer L | title = Highly cooperative opening of calcium channels by inositol 1,4,5-trisphosphate | journal = Science | volume = 240 | issue = 4852 | pages = 653–6 | date = April 1988 | pmid = 2452482 | doi = 10.1126/science.2452482 | bibcode = 1988Sci...240..653M }}</ref> The structure of those receptors shows four IP3 binding sites symmetrically arranged.<ref name=Seo2012>{{cite journal | vauthors = Seo MD, Velamakanni S, Ishiyama N, Stathopulos PB, Rossi AM, Khan SA, Dale P, Li C, Ames JB, Ikura M, Taylor CW | title = Structural and functional conservation of key domains in InsP3 and ryanodine receptors | journal = Nature | volume = 483 | issue = 7387 | pages = 108–12 | date = January 2012 | pmid = 22286060 | pmc = 3378505 | doi = 10.1038/nature10751 | bibcode = 2012Natur.483..108S }}</ref>

=== Multi-site molecules ===
Although most proteins showing cooperative binding are multimeric complexes of homologous subunits, some proteins carry several binding sites for the same ligand on the same polypeptide. One such example is [[calmodulin]]. One molecule of calmodulin binds four calcium ions cooperatively.<ref name=Teo1973>{{cite journal | vauthors = Teo TS, Wang JH | title = Mechanism of activation of a cyclic adenosine 3':5'-monophosphate phosphodiesterase from bovine heart by calcium ions. Identification of the protein activator as a Ca2+ binding protein | journal = The Journal of Biological Chemistry | volume = 248 | issue = 17 | pages = 5950–5 | date = September 1973 | doi = 10.1016/S0021-9258(19)43493-5 | pmid = 4353626 | doi-access = free }}</ref> Its structure presents four [[EF hand|EF-hand domains]],<ref name=Babu1980>{{cite journal | vauthors = Babu YS, Sack JS, Greenhough TJ, Bugg CE, Means AR, Cook WJ | title = Three-dimensional structure of calmodulin | journal = Nature | volume = 315 | issue = 6014 | pages = 37–40 | year = 1985 | pmid = 3990807 | doi = 10.1038/315037a0 | bibcode = 1985Natur.315...37B | s2cid = 4316112 }}</ref> each one binding one calcium ion. The molecule does not display a square or tetrahedron structure, but is formed of two lobes, each carrying two EF-hand domains. [[File:CalmodulinConformation.png|thumb|right|Cartoon representation of the protein Calmodulin in its two conformation: "closed" on the left (derived from [[Protein Data Bank|PDB]] id: 1CFD) and "open" on the right (derived from [[Protein Data Bank|PDB]] id: 3CLN). The open conformation is represented bound with 4 calcium ions (orange spheres).]]

=== Transcription factors ===
Cooperative binding of proteins onto nucleic acids has also been shown. A classical example is the binding of the [[lambda phage]] repressor to its operators, which occurs cooperatively.<ref name=Ptashne1980>{{cite journal | vauthors = Ptashne M, Jeffrey A, Johnson AD, Maurer R, Meyer BJ, Pabo CO, Roberts TM, Sauer RT | title = How the lambda repressor and cro work | journal = Cell | volume = 19 | issue = 1 | pages = 1–11 | date = January 1980 | pmid = 6444544 | doi = 10.1016/0092-8674(80)90383-9 | s2cid = 54281357 }}</ref><ref name=Ackers1982>{{cite journal | vauthors = Ackers GK, Johnson AD, Shea MA | title = Quantitative model for gene regulation by lambda phage repressor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 79 | issue = 4 | pages = 1129–33 | date = February 1982 | pmid = 6461856 | pmc = 345914 | doi = 10.1073/pnas.79.4.1129 | bibcode = 1982PNAS...79.1129A | doi-access = free }}</ref> Other examples of transcription factors exhibit positive cooperativity when binding their target, such as the repressor of the TtgABC pumps<ref name=Krell2007>{{cite journal | vauthors = Krell T, Terán W, Mayorga OL, Rivas G, Jiménez M, Daniels C, Molina-Henares AJ, Martínez-Bueno M, Gallegos MT, Ramos JL | title = Optimization of the palindromic order of the TtgR operator enhances binding cooperativity | journal = Journal of Molecular Biology | volume = 369 | issue = 5 | pages = 1188–99 | date = June 2007 | pmid = 17498746 | doi = 10.1016/j.jmb.2007.04.025 }}</ref> (n=1.6), as well as conditional cooperativity exhibited by the transcription factors [[HOXA11]] and [[FOXO1]].<ref name="Nnamani-et-al-2016">{{cite journal | last1=Nnamani | first1=Mauris C. | display-authors=etal | year=2016 | title=A derived allosteric switch underlies the evolution of conditional cooperativity between HOXA11 and FOXO1 | journal=Cell Reports | volume=15 | issue=10| pages=2097–2108 | doi=10.1016/j.celrep.2016.04.088| pmid=27239043 | doi-access=free | hdl=2437/230273 | hdl-access=free }}</ref>

Conversely, examples of negative cooperativity for the binding of transcription factors were also documented, as for the homodimeric repressor of the ''[[Pseudomonas putida]]'' [[cytochrome P450]]cam hydroxylase operon<ref name=Arakami2011>{{cite journal | vauthors = Aramaki H, Kabata H, Takeda S, Itou H, Nakayama H, Shimamoto N | title = Formation of repressor-inducer-operator ternary complex: negative cooperativity of d-camphor binding to CamR | journal = Genes to Cells | volume = 16 | issue = 12 | pages = 1200–7 | date = December 2011 | pmid = 22093184 | doi = 10.1111/j.1365-2443.2011.01563.x | s2cid = 29006987 | doi-access = free }}</ref> (n=0.56).

=== Conformational spread and binding cooperativity ===
Early on, it has been argued that some proteins, especially those consisting of many subunits, could be regulated by a generalized MWC mechanism, in which the transition between R and T state is not necessarily synchronized across the entire protein.<ref name=Changeux1967>{{cite journal | vauthors = Changeux JP, Thiéry J, Tung Y, Kittel C | title = On the cooperativity of biological membranes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 57 | issue = 2 | pages = 335–41 | date = February 1967 | pmid = 16591474 | pmc = 335510 | doi = 10.1073/pnas.57.2.335 | bibcode = 1967PNAS...57..335C | doi-access = free }}</ref> In 1969, Wyman<ref name=Wyman1969>{{cite journal | vauthors = Wyman J | title = Possible allosteric effects in extended biological systems | journal = Journal of Molecular Biology | volume = 39 | issue = 3 | pages = 523–38 | date = February 1969 | pmid = 5357210 | doi = 10.1016/0022-2836(69)90142-9 }}</ref> proposed such a model with "mixed conformations" (i.e. some protomers in the R state, some in the T state) for respiratory proteins in invertebrates.

Following a similar idea, the conformational spread model by Duke and colleagues<ref name=Duke2001>{{cite journal | vauthors = Duke TA, Le Novère N, Bray D | s2cid = 14914075 | title = Conformational spread in a ring of proteins: a stochastic approach to allostery | journal = Journal of Molecular Biology | volume = 308 | issue = 3 | pages = 541–53 | date = May 2001 | pmid = 11327786 | doi = 10.1006/jmbi.2001.4610 }}</ref> subsumes both the KNF and the MWC model as special cases. In this model, a subunit does not automatically change conformation upon ligand binding (as in the KNF model), nor do all subunits in a complex change conformations together (as in the MWC model). Conformational changes are stochastic with the likelihood of a subunit switching states depending on whether or not it is ligand bound and on the conformational state of neighbouring subunits. Thus, conformational states can "spread" around the entire complex.