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→Mechanism: Add a paragraph describing calmodulin's binding behavior toward ions other than calcium, which is not otherwise addressed in the article. |
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Calcium binding by calmodulin exhibits considerable [[cooperativity]],<ref name="OZHAc" /><ref name="kPKSE" /> making calmodulin an unusual example of a monomeric (single-chain) cooperative-binding protein. Furthermore, target binding alters the binding affinity of calmodulin toward Ca<sup>2+</sup> ions,<ref>{{cite journal | vauthors = Johnson JD, Snyder C, Walsh M, Flynn M | s2cid = 9746955 | title = Effects of myosin light chain kinase and peptides on Ca2+ exchange with the N- and C-terminal Ca2+ binding sites of calmodulin | journal = The Journal of Biological Chemistry | volume = 271 | issue = 2 | pages = 761–7 | date = January 1996 | pmid = 8557684 | doi = 10.1074/jbc.271.2.761 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Bayley PM, Findlay WA, Martin SR | title = Target recognition by calmodulin: dissecting the kinetics and affinity of interaction using short peptide sequences | journal = Protein Science | volume = 5 | issue = 7 | pages = 1215–28 | date = July 1996 | pmid = 8819155 | doi = 10.1002/pro.5560050701 | pmc = 2143466 }}</ref><ref>{{cite journal | vauthors = Theoharis NT, Sorensen BR, Theisen-Toupal J, Shea MA | title = The neuronal voltage-dependent sodium channel type II IQ motif lowers the calcium affinity of the C-domain of calmodulin | journal = Biochemistry | volume = 47 | issue = 1 | pages = 112–23 | date = January 2008 | pmid = 18067319 | doi = 10.1021/bi7013129 }}</ref> which allows for complex [[allosteric]] interplay between Ca<sup>2+</sup> and target binding interactions.<ref>{{cite journal | vauthors = Stefan MI, Edelstein SJ, Le Novère N | title = An allosteric model of calmodulin explains differential activation of PP2B and CaMKII | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 31 | pages = 10768–73 | date = August 2008 | pmid = 18669651 | doi = 10.1073/pnas.0804672105 | pmc = 2504824 | bibcode = 2008PNAS..10510768S }}</ref> This influence of target binding on Ca<sup>2+</sup> affinity is believed to allow for Ca<sup>2+</sup> activation of proteins that are constitutively bound to calmodulin, such as small-conductance Ca<sup>2+</sup>-activated potassium (SK) channels.<ref>{{cite journal | vauthors = Zhang M, Abrams C, Wang L, Gizzi A, He L, Lin R, Chen Y, Loll PJ, Pascal JM, Zhang JF | display-authors = 6 | title = Structural basis for calmodulin as a dynamic calcium sensor | journal = Structure | volume = 20 | issue = 5 | pages = 911–23 | date = May 2012 | pmid = 22579256 | doi = 10.1016/j.str.2012.03.019 | pmc = 3372094 }}</ref>
Although calmodulin principally operates as a Ca<sup>2+</sup> binding protein, it also coordinates other metal ions. For example, in the presence of typical intracellular concentrations of Mg<sup>2+</sup> (0.5 - 1.0 mM) and resting concentrations of Ca<sup>2+</sup> (100 nM), calmodulin's Ca<sup>2+</sup> binding sites are at least partially saturated by Mg<sup>2+</sup><ref>{{Cite journal|date=2011-05-01|title=Insights into modulation of calcium signaling by magnesium in calmodulin, troponin C and related EF-hand proteins|url=https://www.sciencedirect.com/science/article/pii/S0167488911000255|journal=Biochimica et Biophysica Acta (BBA) - Molecular Cell Research|language=en|volume=1813|issue=5|pages=913–921|doi=10.1016/j.bbamcr.2011.01.017|issn=0167-4889}}</ref>. This Mg<sup>2+</sup> is displaced by the higher concentrations of Ca<sup>2+</sup> generated by signaling events. Similarly, Ca<sup>2+</sup> may itself be displaced by other metal ions, such as the trivalent lanthanides, that associate with calmodulin's binding pockets even more strongly than Ca<sup>2+</sup><ref name=":0">{{Cite journal|last=Brittain|first=H. G.|last2=Richardson|first2=F. S.|last3=Martin|first3=R. B.|date=1976-12-08|title=Terbium (III) emission as a probe of calcium(II) binding sites in proteins|url=https://pubmed.ncbi.nlm.nih.gov/993525/|journal=Journal of the American Chemical Society|volume=98|issue=25|pages=8255–8260|doi=10.1021/ja00441a060|issn=0002-7863|pmid=993525}}</ref><ref>{{Cite journal|last=Kilhoffer|first=M. C.|last2=Demaille|first2=J. G.|last3=Gerard|first3=D.|date=1980-07-28|title=Terbium as luminescent probe of calmodulin calcium-binding sites; domains I and II contain the high-affinity sites|url=https://pubmed.ncbi.nlm.nih.gov/7409149/?dopt=Abstract|journal=FEBS letters|volume=116|issue=2|pages=269–272|doi=10.1016/0014-5793(80)80660-0|issn=0014-5793|pmid=7409149}}</ref>. Though such ions distort calmodulin's structure<ref>{{Cite journal|last=Edington|first=Sean C.|last2=Gonzalez|first2=Andrea|last3=Middendorf|first3=Thomas R.|last4=Halling|first4=D. Brent|last5=Aldrich|first5=Richard W.|last6=Baiz|first6=Carlos R.|date=2018-04-03|title=Coordination to lanthanide ions distorts binding site conformation in calmodulin|url=https://www.pnas.org/content/115/14/E3126|journal=Proceedings of the National Academy of Sciences|language=en|volume=115|issue=14|pages=E3126–E3134|doi=10.1073/pnas.1722042115|issn=0027-8424|pmid=29545272}}</ref><ref>{{Cite journal|last=Chao|first=S. H.|last2=Suzuki|first2=Y.|last3=Zysk|first3=J. R.|last4=Cheung|first4=W. Y.|date=1984-07-01|title=Activation of calmodulin by various metal cations as a function of ionic radius.|url=https://molpharm.aspetjournals.org/content/26/1/75|journal=Molecular Pharmacology|language=en|volume=26|issue=1|pages=75–82|issn=0026-895X|pmid=6087119}}</ref> and are generally not physiologically relevant due to their scarcity ''in vitro'', they have nonetheless seen wide scientific use as reporters of calmodulin structure and function<ref>{{Cite journal|last=Horrocks|first=William D.|last2=Sudnick|first2=Daniel R.|date=1981-12-01|title=Lanthanide ion luminescence probes of the structure of biological macromolecules|url=https://doi.org/10.1021/ar00072a004|journal=Accounts of Chemical Research|volume=14|issue=12|pages=384–392|doi=10.1021/ar00072a004|issn=0001-4842}}</ref><ref>{{Cite journal|last=Mulqueen|first=P.|last2=Tingey|first2=J. M.|last3=Horrocks|first3=W. D.|date=1985-11-05|title=Characterization of lanthanide (III) ion binding to calmodulin using luminescence spectroscopy|url=https://pubmed.ncbi.nlm.nih.gov/4084548/?dopt=Abstract|journal=Biochemistry|volume=24|issue=23|pages=6639–6645|doi=10.1021/bi00344a051|issn=0006-2960|pmid=4084548}}</ref><ref name=":0" />.
==Role in animals==
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