Editing Calmodulin (section)

== Structure ==
Calmodulin is a small, highly conserved protein that is 148 amino acids long (16.7 kDa). The protein has two approximately symmetrical globular domains (the N- and C- domains) each containing a pair of [[EF hand]] [[Sequence motif|motifs]]<ref name="OZHAc">{{cite journal | vauthors = Gifford JL, Walsh MP, Vogel HJ | title = Structures and metal-ion-binding properties of the Ca2+-binding helix-loop-helix EF-hand motifs | journal = The Biochemical Journal | volume = 405 | issue = 2 | pages = 199–221 | date = July 2007 | pmid = 17590154 | doi = 10.1042/BJ20070255 }}</ref> separated by a flexible linker region for a total of four Ca<sup>2+</sup> binding sites, two in each globular domain.<ref name="CA3BC">{{cite journal | vauthors = Chin D, Means AR | title = Calmodulin: a prototypical calcium sensor | journal = Trends in Cell Biology | volume = 10 | issue = 8 | pages = 322–8 | date = August 2000 | pmid = 10884684 | doi = 10.1016/s0962-8924(00)01800-6 }}</ref>  In the Ca<sup>2+</sup>-free state, the helices that form the four EF-hands are collapsed in a compact orientation, and the central linker is disordered;<ref name="OZHAc" /><ref name="CA3BC" /><ref>{{cite journal | vauthors = Kuboniwa H, Tjandra N, Grzesiek S, Ren H, Klee CB, Bax A | s2cid = 22220229 | title = Solution structure of calcium-free calmodulin | journal = Nature Structural Biology | volume = 2 | issue = 9 | pages = 768–76 | date = September 1995 | pmid = 7552748 | doi = 10.1038/nsb0995-768 }}</ref><ref>{{cite journal | vauthors = Zhang M, Tanaka T, Ikura M | s2cid = 35098883 | title = Calcium-induced conformational transition revealed by the solution structure of apo calmodulin | journal = Nature Structural Biology | volume = 2 | issue = 9 | pages = 758–67 | date = September 1995 | pmid = 7552747 | doi = 10.1038/nsb0995-758 }}</ref>  in the Ca<sup>2+</sup>-saturated state, the EF-hand helices adopt an open orientation roughly perpendicular to one another, and the central linker forms an extended alpha-helix in the crystal structure,<ref name="OZHAc" /><ref name="CA3BC" /> but remains largely disordered in solution.<ref name="CYhOa">{{cite journal | vauthors = Chou JJ, Li S, Klee CB, Bax A | s2cid = 4665648 | title = Solution structure of Ca(2+)-calmodulin reveals flexible hand-like properties of its domains | journal = Nature Structural Biology | volume = 8 | issue = 11 | pages = 990–7 | date = November 2001 | pmid = 11685248 | doi = 10.1038/nsb1101-990 }}</ref>  The C-domain has a higher binding affinity for Ca<sup>2+</sup> than the N-domain.<ref>{{cite journal | vauthors = Yang JJ, Gawthrop A, Ye Y | title = Obtaining site-specific calcium-binding affinities of calmodulin | journal = Protein and Peptide Letters | volume = 10 | issue = 4 | pages = 331–45 | date = August 2003 | pmid = 14529487 | doi = 10.2174/0929866033478852 }}</ref><ref name="kPKSE">{{cite journal | vauthors = Linse S, Helmersson A, Forsén S | title = Calcium binding to calmodulin and its globular domains | journal = The Journal of Biological Chemistry | volume = 266 | issue = 13 | pages = 8050–4 | date = May 1991 | doi = 10.1016/S0021-9258(18)92938-8 | pmid = 1902469 | doi-access = free }}</ref>

Calmodulin is structurally quite similar to [[troponin C]], another Ca<sup>2+</sup>-binding protein containing four EF-hand motifs.<ref name="OZHAc" /><ref>{{cite journal | vauthors = Houdusse A, Love ML, Dominguez R, Grabarek Z, Cohen C | title = Structures of four Ca2+-bound troponin C at 2.0 A resolution: further insights into the Ca2+-switch in the calmodulin superfamily | journal = Structure | volume = 5 | issue = 12 | pages = 1695–711 | date = December 1997 | pmid = 9438870 | doi = 10.1016/s0969-2126(97)00315-8 | doi-access = free }}</ref>  However, troponin C contains an additional alpha-helix at its N-terminus, and is constitutively bound to its target, [[troponin I]].  It therefore does not exhibit the same diversity of target recognition as does calmodulin.

=== Importance of flexibility in calmodulin ===
Calmodulin's ability to recognize a tremendous range of target proteins is due in large part to its structural flexibility.<ref>{{cite journal | vauthors = Yamniuk AP, Vogel HJ | s2cid = 26585744 | title = Calmodulin's flexibility allows for promiscuity in its interactions with target proteins and peptides | journal = Molecular Biotechnology | volume = 27 | issue = 1 | pages = 33–57 | date = May 2004 | pmid = 15122046 | doi = 10.1385/MB:27:1:33 }}</ref>  In addition to the flexibility of the central linker domain, the N- and C-domains undergo open-closed conformational cycling in the Ca<sup>2+</sup>-bound state.<ref name="CYhOa" />  Calmodulin also exhibits great structural variability, and undergoes considerable conformational fluctuations, when bound to targets.<ref name="Tidow_2013">{{cite journal | vauthors = Tidow H, Nissen P | title = Structural diversity of calmodulin binding to its target sites | journal = The FEBS Journal | volume = 280 | issue = 21 | pages = 5551–65 | date = November 2013 | pmid = 23601118 | doi = 10.1111/febs.12296 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Frederick KK, Marlow MS, Valentine KG, Wand AJ | title = Conformational entropy in molecular recognition by proteins | journal = Nature | volume = 448 | issue = 7151 | pages = 325–9 | date = July 2007 | pmid = 17637663 | doi = 10.1038/nature05959 | pmc = 4156320 | bibcode = 2007Natur.448..325F }}</ref><ref>{{cite journal | vauthors = Gsponer J, Christodoulou J, Cavalli A, Bui JM, Richter B, Dobson CM, Vendruscolo M | title = A coupled equilibrium shift mechanism in calmodulin-mediated signal transduction | journal = Structure | volume = 16 | issue = 5 | pages = 736–46 | date = May 2008 | pmid = 18462678 | doi = 10.1016/j.str.2008.02.017 | pmc = 2428103 }}</ref> Moreover, the predominantly hydrophobic nature of binding between calmodulin and most of its targets allows for recognition of a broad range of target protein sequences.<ref name="Tidow_2013" /><ref>{{cite journal | vauthors = Ishida H, Vogel HJ | title = Protein-peptide interaction studies demonstrate the versatility of calmodulin target protein binding | journal = Protein and Peptide Letters | volume = 13 | issue = 5 | pages = 455–65 | date = 2006 | pmid = 16800798 | doi = 10.2174/092986606776819600 }}</ref>  Together, these features allow calmodulin to recognize some 300 target proteins<ref name="vCsmX">{{cite web |title=Calmodulin Target Database |url=http://calcium.uhnres.utoronto.ca/ctdb/ |access-date=27 July 2020 |archive-date=31 January 2023 |archive-url=https://web.archive.org/web/20230131125456/http://calcium.uhnres.utoronto.ca/ctdb/ |url-status=dead }}</ref> exhibiting a variety of CaM-binding sequence motifs.