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Calmodulin
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==Mechanism== [[File:Calmodulin Binding sites.gif|thumb|This images shows conformational changes in calmodulin. On the left is calmodulin without calcium and on the right is calmodulin with calcium. Sites that bind target proteins are indicated by red stars.]] [[File:Calmodulin C-terminal.jpg|thumb|Solution structure of Ca<sup>2+</sup>-calmodulin ''C''-terminal domain]] [[File:Calmodulin N-terminal.jpg|thumb|Solution structure of Ca<sup>2+</sup>-calmodulin ''N''-terminal domain]] Binding of Ca<sup>2+</sup> by the EF-hands causes an opening of the N- and C-domains, which exposes hydrophobic target-binding surfaces.<ref name="CA3BC" /> These surfaces interact with complementary nonpolar segments on target proteins, typically consisting of groups of bulky hydrophobic amino acids separated by 10β16 polar and/or basic amino acids.<ref name="vCsmX" /><ref name="Tidow_2013" /> The flexible central domain of calmodulin allows the protein to wrap around its target, although alternate modes of binding are known. "Canonical" targets of calmodulin, such as myosin light-chain kinases and [[CaMKII]], bind only to the Ca<sup>2+</sup>-bound protein, whereas some proteins, such as [[Sodium channel|NaV channels]] and [[IQ-motif]] proteins, also bind to calmodulin in the absence of Ca<sup>2+</sup>.<ref name="Tidow_2013" /> Binding of calmodulin induces conformational rearrangements in the target protein via "mutually induced fit",<ref>{{cite journal | vauthors = Wang Q, Zhang P, Hoffman L, Tripathi S, Homouz D, Liu Y, Waxham MN, Cheung MS | display-authors = 6 | title = Protein recognition and selection through conformational and mutually induced fit | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 51 | pages = 20545β50 | date = December 2013 | pmid = 24297894 | doi = 10.1073/pnas.1312788110 | pmc = 3870683 | bibcode = 2013PNAS..11020545W | doi-access = free }}</ref> leading to changes in the target protein's function. 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 = 761β7 | 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 = 1215β28 | 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 = 112β23 | 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 NovΓ¨re 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 = 10768β73 | date = August 2008 | pmid = 18669651 | doi = 10.1073/pnas.0804672105 | pmc = 2504824 | bibcode = 2008PNAS..10510768S | doi-access = free }}</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 = 911β23 | 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> (0.5β1.0 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 | vauthors = Grabarek Z | title = Insights into modulation of calcium signaling by magnesium in calmodulin, troponin C and related EF-hand proteins | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1813 | issue = 5 | pages = 913β21 | date = May 2011 | pmid = 21262274 | doi = 10.1016/j.bbamcr.2011.01.017 | pmc = 3078997 }}</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="Brittain-1976">{{cite journal | vauthors = Brittain HG, Richardson FS, Martin RB | title = Terbium (III) emission as a probe of calcium(II) binding sites in proteins | journal = Journal of the American Chemical Society | volume = 98 | issue = 25 | pages = 8255β60 | date = December 1976 | pmid = 993525 | doi = 10.1021/ja00441a060 }}</ref><ref>{{cite journal | vauthors = Kilhoffer MC, Demaille JG, Gerard D | title = Terbium as luminescent probe of calmodulin calcium-binding sites; domains I and II contain the high-affinity sites | journal = FEBS Letters | volume = 116 | issue = 2 | pages = 269β72 | date = July 1980 | pmid = 7409149 | doi = 10.1016/0014-5793(80)80660-0 | doi-access = free | bibcode = 1980FEBSL.116..269K }}</ref> Though such ions distort calmodulin's structure<ref>{{cite journal | vauthors = Edington SC, Gonzalez A, Middendorf TR, Halling DB, Aldrich RW, Baiz CR | title = Coordination to lanthanide ions distorts binding site conformation in calmodulin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 115 | issue = 14 | pages = E3126βE3134 | date = April 2018 | pmid = 29545272 | doi = 10.1073/pnas.1722042115 | pmc = 5889669 | bibcode = 2018PNAS..115E3126E | doi-access = free }}</ref><ref>{{cite journal | vauthors = Chao SH, Suzuki Y, Zysk JR, Cheung WY | title = Activation of calmodulin by various metal cations as a function of ionic radius | journal = Molecular Pharmacology | volume = 26 | issue = 1 | pages = 75β82 | date = July 1984 | pmid = 6087119 | url = https://molpharm.aspetjournals.org/content/26/1/75 }}</ref> and are generally not physiologically relevant due to their scarcity ''in vivo'', they have nonetheless seen wide scientific use as reporters of calmodulin structure and function.<ref>{{Cite journal| vauthors = Horrocks Jr WD, Sudnick DR |date=1981-12-01|title=Lanthanide ion luminescence probes of the structure of biological macromolecules |journal=Accounts of Chemical Research|volume=14|issue=12|pages=384β392|doi=10.1021/ar00072a004|issn=0001-4842}}</ref><ref>{{cite journal | vauthors = Mulqueen P, Tingey JM, Horrocks WD | title = Characterization of lanthanide (III) ion binding to calmodulin using luminescence spectroscopy | journal = Biochemistry | volume = 24 | issue = 23 | pages = 6639β45 | date = November 1985 | pmid = 4084548 | doi = 10.1021/bi00344a051 }}</ref><ref name="Brittain-1976" />
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