View source for Calmodulin

{{Short description|Messenger protein}}
{{More citations needed|date=December 2007}}
{{Infobox protein
| name       = Calmodulin
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| image      = Calmodulin.png
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| caption    = 3D structure of Ca<sup>2+</sup>-bound calmodulin ({{PDB|1OSA}})
| Symbol     = CaM
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| PDB        = 1OSA
| RefSeq     = 
| UniProt    = P62158
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}}

[[File:EFhandmotif.jpg|thumb|The helix–loop–helix structure of the calcium-binding [[EF hand]] motif]]
'''Calmodulin''' ('''CaM''') (an abbreviation for '''cal'''cium-'''modul'''ated prote'''in''') is a multifunctional intermediate calcium-binding messenger protein expressed in all [[Eukaryote|eukaryotic cells]].<ref>{{cite journal | vauthors = Stevens FC | title = Calmodulin: an introduction | journal = Canadian Journal of Biochemistry and Cell Biology | volume = 61 | issue = 8 | pages = 906–10 | date = August 1983 | pmid = 6313166 | doi = 10.1139/o83-115 }}</ref> It is an intracellular target of the [[Second messenger system|secondary messenger]] [[Calcium in biology|Ca<sup>2+</sup>]], and the binding of Ca<sup>2+</sup> is required for the activation of calmodulin. Once bound to Ca<sup>2+</sup>, calmodulin acts as part of a calcium [[Signal transduction|signal transduction pathway]] by modifying its interactions with various target proteins such as [[kinase]]s or [[phosphatase]]s.<ref>{{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><ref>{{cite book| vauthors = Purves D, Augustine G, Fitzpatrick D, Hall W, LaMantia AS, White L |date=2012 |title=Neuroscience |location=Massachusetts |publisher=Sinauer Associates |pages=95, 147, 148 |isbn=9780878936953}}</ref><ref name="uniprot">{{Cite web|title = CALM1 – Calmodulin – ''Homo sapiens'' (Human) – CALM1 gene & protein|url = https://www.uniprot.org/uniprot/P62158|website = www.uniprot.org|access-date = 2016-02-23}}</ref>

== 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.

==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 10–16 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 = 20545–50 | 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 = 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 | 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 = 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 | 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 = 913–21 | 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 = 8255–60 | 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 = 269–72 | 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 = E3126–E3134 | 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 = 75–82 | 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=384–392|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 = 6639–45 | date = November 1985 | pmid = 4084548 | doi = 10.1021/bi00344a051 }}</ref><ref name="Brittain-1976" />

==Role in animals==
Calmodulin mediates many crucial processes such as [[inflammation]], [[metabolism]], [[apoptosis]], [[smooth muscle]] contraction, intracellular movement, [[short-term memory|short-term]] and [[long-term memory]], and the [[immune response]].<ref>{{Cite web|title = Home Page for Calmodulin|url = http://structbio.vanderbilt.edu/cabp_database/general/prot_pages/calmod.html#func|website = structbio.vanderbilt.edu|access-date = 2016-02-23}}</ref><ref name="McDowall">{{Cite web|url = https://www.ebi.ac.uk/interpro/potm/2003_3/Page_1.htm|title = Calmodulin|access-date = 23 February 2016|website = InterPro Protein Archive| vauthors  = McDowall J }}</ref> Calcium participates in an [[Cell signaling|intracellular signaling]] system by acting as a diffusible second messenger to the initial stimuli. It does this by binding various targets in the cell including a large number of [[enzyme]]s, [[ion channel]]s, [[aquaporin]]s and other proteins.<ref name="uniprot" /> Calmodulin is expressed in many cell types and can have different subcellular locations, including the [[cytoplasm]], within [[organelle]]s, or associated with the [[plasma membrane|plasma]] or organelle membranes, but it is always found intracellularly.<ref name="McDowall" />  Many of the proteins that calmodulin binds are unable to bind calcium themselves, and use calmodulin as a calcium sensor and signal transducer. Calmodulin can also make use of the calcium stores in the [[endoplasmic reticulum]], and the [[sarcoplasmic reticulum]].  Calmodulin can undergo post-translational modifications, such as [[phosphorylation]], [[acetylation]], [[methylation]] and [[proteolytic cleavage]], each of which has potential to modulate its actions.

=== Specific examples ===

==== Role in smooth muscle contraction ====
[[File:Calmodulin bound to MLC Kinase.jpg|thumb|Calmodulin bound to a peptide from MLC kinase ({{PDB|2LV6}})]]
Calmodulin plays an important role in [[Excitation contraction coupling|excitation contraction (EC) coupling]] and the initiation of the cross-bridge cycling in [[Smooth muscle tissue|smooth muscle]], ultimately causing smooth muscle contraction.<ref name="Tansey-1994">{{cite journal | vauthors = Tansey MG, Luby-Phelps K, Kamm KE, Stull JT | title = Ca(2+)-dependent phosphorylation of myosin light chain kinase decreases the Ca2+ sensitivity of light chain phosphorylation within smooth muscle cells | journal = The Journal of Biological Chemistry | volume = 269 | issue = 13 | pages = 9912–20 | date = April 1994 | doi = 10.1016/S0021-9258(17)36969-7 | pmid = 8144585 | url = http://www.jbc.org/content/269/13/9912 | doi-access = free }}</ref> In order to activate contraction of smooth muscle, the head of the [[myosin light chain]] must be phosphorylated. This phosphorylation is done by [[Myosin light-chain kinase|myosin light chain (MLC) kinase]]. This MLC kinase is activated by a calmodulin when it is bound by calcium, thus making smooth muscle contraction dependent on the presence of calcium, through the binding of calmodulin and activation of MLC kinase.<ref name="Tansey-1994" />

Another way that calmodulin affects muscle contraction is by controlling the movement of Ca<sup>2+</sup> across both the cell and [[sarcoplasmic reticulum]] membranes. The [[Calcium channels|Ca<sup>2+</sup> channels]], such as the [[ryanodine receptor]] of the sarcoplasmic reticulum, can be inhibited by calmodulin bound to calcium, thus affecting the overall levels of calcium in the cell.<ref>{{cite journal | vauthors = Walsh MP | s2cid = 2304136 | title = Calmodulin and the regulation of smooth muscle contraction | journal = Molecular and Cellular Biochemistry | volume = 135 | issue = 1 | pages = 21–41 | date = June 1994 | pmid = 7816054 | doi = 10.1007/bf00925958 }}</ref> Calcium pumps take calcium out of the cytoplasm or store it in the [[endoplasmic reticulum]] and this control helps regulate many downstream processes.

This is a very important function of calmodulin because it indirectly plays a role in every physiological process that is affected by [[Smooth muscle tissue|smooth muscle]] contraction such as digestion and contraction of arteries (which helps distribute blood and regulate [[blood pressure]]).<ref>{{cite journal | vauthors = Martinsen A, Dessy C, Morel N | title = Regulation of calcium channels in smooth muscle: new insights into the role of myosin light chain kinase | journal = Channels | volume = 8 | issue = 5 | pages = 402–13 | date = 2014-10-31 | pmid = 25483583 | pmc = 4594426 | doi = 10.4161/19336950.2014.950537 }}</ref>

==== Role in metabolism ====
Calmodulin plays an important role in the activation of [[phosphorylase kinase]], which ultimately leads to [[glucose]] being cleaved from [[glycogen]] by [[glycogen phosphorylase]].<ref name="Nishizawa-1988">{{cite journal | vauthors = Nishizawa Y, Okui Y, Inaba M, Okuno S, Yukioka K, Miki T, Watanabe Y, Morii H | display-authors = 6 | title = Calcium/calmodulin-mediated action of calcitonin on lipid metabolism in rats | journal = The Journal of Clinical Investigation | volume = 82 | issue = 4 | pages = 1165–72 | date = October 1988 | pmid = 2844851 | pmc = 442666 | doi = 10.1172/jci113713 }}</ref>

Calmodulin also plays an important role in [[lipid metabolism]] by affecting [[Calcitonin gene-related peptide|calcitonin]]. Calcitonin is a polypeptide hormone that lowers blood Ca<sup>2+</sup> levels and activates [[G protein|Gs protein]] cascades that leads to the generation of cAMP. The actions of calcitonin can be blocked by inhibiting the actions of calmodulin, suggesting that calmodulin plays a crucial role in the activation of calcitonin.<ref name="Nishizawa-1988" />

==== Role in short-term and long-term memory ====
[[Ca2+/calmodulin-dependent protein kinase II|Ca<sup>2+</sup>/calmodulin-dependent protein kinase II]] (CaMKII) plays a crucial role in a type of synaptic plasticity known as [[long-term potentiation]] (LTP) which requires the presence of calcium/calmodulin. CaMKII contributes to the [[phosphorylation]] of an [[AMPA receptor]] which increases the sensitivity of AMPA receptors.<ref name="Lledo-1995">{{cite journal | vauthors = Lledo PM, Hjelmstad GO, Mukherji S, Soderling TR, Malenka RC, Nicoll RA | title = Calcium/calmodulin-dependent kinase II and long-term potentiation enhance synaptic transmission by the same mechanism | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 24 | pages = 11175–9 | date = November 1995 | pmid = 7479960 | pmc = 40594 | doi = 10.1073/pnas.92.24.11175 | bibcode = 1995PNAS...9211175L | doi-access = free }}</ref> Furthermore, research shows that inhibiting CaMKII interferes with LTP.<ref name="Lledo-1995" />

==  Role in plants ==
{{Unreferenced section|date=March 2020}}
[[File:Sorghum bicolor (4171536532).jpg|right|thumb|[[Sorghum]] plant contains temperature-responsive genes. These [[genes]] help the plant [[Adaptation|adapt]] in extreme weather conditions such as hot and dry [[Natural environment|environment]]s.]]
While yeasts have only a single CaM gene, plants and vertebrates contain an evolutionarily conserved form of CaM genes. The difference between plants and animals in Ca<sup>2+</sup> signaling is that the plants contain an extended family of the CaM in addition to the evolutionarily conserved form.<ref>{{cite journal | vauthors = Ranty B, Aldon D, Galaud JP | title = Plant calmodulins and calmodulin-related proteins: multifaceted relays to decode calcium signals | journal = Plant Signaling & Behavior | volume = 1 | issue = 3 | pages = 96–104 | date = May 2006 | pmid = 19521489 | pmc = 2635005 | doi = 10.4161/psb.1.3.2998 }}</ref> Calmodulins play an essential role in plant development and adaptation to environmental stimuli.

Calcium plays a key role in the structural integrity of the cell wall and the membrane system of the cell. However, high calcium levels can be toxic to a plant's cellular energy metabolism and, hence, the Ca<sup>2+</sup> concentration in the cytosol is maintained at a submicromolar level by removing the cytosolic Ca<sup>2+</sup> to either the [[apoplast]] or the lumen of the intracellular organelles. Ca<sup>2+</sup> pulses created due to increased influx and efflux act as cellular signals in response to external stimuli such as hormones, light, gravity, abiotic stress factors and also interactions with pathogens.<ref>{{Cite journal |last1=Virdi |first1=Amardeep S. |last2=Singh |first2=Supreet |last3=Singh |first3=Prabhjeet |date=2015 |title=Abiotic stress responses in plants: roles of calmodulin-regulated proteins |journal=Frontiers in Plant Science |volume=6 |page=809 |doi=10.3389/fpls.2015.00809 |pmid=26528296 |pmc=4604306 |issn=1664-462X|doi-access=free }}</ref>

=== CMLs (CaM-related proteins) ===
Plants contain CaM-related proteins (CMLs) apart from the typical CaM proteins. The CMLs have about 15% amino acid similarity with the typical CaMs. ''[[Arabidopsis thaliana]]'' contains about 50 different CML genes,<ref>{{Cite journal |last1=Yang |first1=Dong |last2=Chen |first2=Ting |last3=Wu |first3=Yushuang |last4=Tang |first4=Huiquan |last5=Yu |first5=Junyi |last6=Dai |first6=Xiaoqiu |last7=Zheng |first7=Yixiong |last8=Wan |first8=Xiaorong |last9=Yang |first9=Yong |last10=Tan |first10=Xiaodan |date=2024-02-21 |title=Genome-wide analysis of the peanut CaM/CML gene family reveals that the AhCML69 gene is associated with resistance to Ralstonia solanacearum |journal=BMC Genomics |volume=25 |issue=1 |pages=200 |doi=10.1186/s12864-024-10108-5 |doi-access=free |issn=1471-2164 |pmc=10880322 |pmid=38378471}}</ref> which leads to the question of what purpose these diverse ranges of proteins serve in the cellular function. All plant species exhibit this diversity in the CML genes. The different CaMs and CMLs differ in their affinity to bind and activate the CaM-regulated enzymes ''in vivo''. The CaM or CMLs are also found to be located in different organelle compartments.

===Plant growth and development===
In ''Arabidopsis,'' the protein [[DWF1]] plays an enzymatic role in the biosynthesis of brassinosteroids, steroid hormones in plants that are required for growth. An interaction occurs between CaM and DWF1,{{Clarify|reason="An interaction" is not specific enough|date=March 2020}} and DWF1 being unable to bind CaM is unable to produce a regular growth phenotype in plants. Hence, CaM is essential for the DWF1 function in plant growth.

CaM binding proteins are also known to regulate reproductive development in plants. For instance, the CaM-binding protein kinase in tobacco acts as a negative regulator of flowering. However, these CaM-binding protein kinase are also present in the shoot [[Apical Meristem|apical meristem]] of tobacco and a high concentration of these kinases in the meristem causes a delayed transition to flowering in the plant.

''S''-locus receptor kinase (SRK) is another protein kinase that interacts with CaM. SRK is involved in the self-incompatibility responses involved in pollen-pistil interactions in ''[[Brassica]]''.

CaM targets in ''Arabidopsis'' are also involved in pollen development and fertilization. Ca<sup>2+</sup> transporters are essential for [[pollen tube]] growth. Hence, a constant Ca<sup>2+</sup> gradient is maintained at the apex of pollen tube for elongation during the process of fertilization. Similarly, CaM is also essential at the pollen tube apex, where its primarily role involves the guidance of the pollen tube growth.

===Interaction with microbes===
====Nodule formation====
Ca<sup>2+</sup> plays an important role in nodule formation in legumes. Nitrogen is an essential element required in plants and many legumes, unable to fix nitrogen independently, pair symbiotically with nitrogen-fixing bacteria that reduce nitrogen to ammonia. This legume-''[[Rhizobium]]'' interaction establishment requires the Nod factor that is produced by the ''Rhizobium'' bacteria. The [[Nod factor]] is recognized by the root hair cells that are involved in the nodule formation in legumes. Ca<sup>2+</sup> responses of varied nature are characterized to be involved in the Nod factor recognition. There is a Ca<sup>2+</sup> flux at the tip of the root hair initially followed by repetitive oscillation of Ca<sup>2+</sup> in the cytosol and also Ca<sup>2+</sup> spike occurs around the nucleus. DMI3, an essential gene for Nod factor signaling functions downstream of the Ca<sup>2+</sup> spiking signature, might be recognizing the Ca<sup>2+</sup> signature. Further, several CaM and CML genes in ''[[Medicago]]'' and ''Lotus'' are expressed in nodules.

====Pathogen defense====
Among the diverse range of defense strategies plants utilize against pathogens, Ca<sup>2+</sup> signaling is very common. Free Ca<sup>2+</sup> levels in the cytoplasm increases in response to a pathogenic infection. Ca<sup>2+</sup> signatures of this nature usually activate the plant defense system by inducing defense-related genes and the hypersensitive cell death. CaMs, CMLs and CaM-binding proteins are some of the recently identified elements of the plant defense signaling pathways. Several CML genes in [[tobacco]], bean and tomato are responsive to pathogens. CML43 is a CaM-related protein that, as isolated from APR134 gene in the disease-resistant leaves of ''Arabidopsis'' for gene expression analysis, is rapidly induced when the leaves are inoculated with ''[[Pseudomonas syringae]]''. These genes are also found in tomatoes (''Solanum lycopersicum''). The CML43 from the APR134 also binds to Ca<sup>2+</sup> ions in vitro which shows that CML43 and APR134 are, hence, involved in the Ca<sup>2+</sup>-dependent signaling during the plant immune response to bacterial pathogens.<ref>{{cite journal | vauthors = Chiasson D, Ekengren SK, Martin GB, Dobney SL, Snedden WA | s2cid = 1572549 | title = Calmodulin-like proteins from Arabidopsis and tomato are involved in host defense against Pseudomonas syringae pv. tomato | journal = Plant Molecular Biology | volume = 58 | issue = 6 | pages = 887–897 | date = August 2005 | pmid = 16240180 | doi = 10.1007/s11103-005-8395-x }}</ref> The CML9 expression in ''Arabidopsis thaliana'' is rapidly induced by phytopathogenic bacteria, [[flagellin]] and salicylic acid.<ref>{{cite journal | vauthors = Leba LJ, Cheval C, Ortiz-Martín I, Ranty B, Beuzón CR, Galaud JP, Aldon D | title = CML9, an Arabidopsis calmodulin-like protein, contributes to plant innate immunity through a flagellin-dependent signalling pathway | journal = The Plant Journal | volume = 71 | issue = 6 | pages = 976–89 | date = September 2012 | pmid = 22563930 | doi = 10.1111/j.1365-313x.2012.05045.x | doi-access = free }}</ref> Expression of soybean SCaM4 and SCaM5 in transgenic ''tobacco'' and ''Arabidopsis'' causes an activation of genes related to pathogen resistance and also results in enhanced resistance to a wide spectrum of pathogen infection. The same is not true for soybean SCaM1 and SCaM2 that are highly conserved CaM isoforms. The ''At''BAG6 protein is a CaM-binding protein that binds to CaM only in the absence of Ca<sup>2+</sup> and not in the presence of it. ''At''BAG6 is responsible for the hypersensitive response of programmed cell death in order to prevent the spread of pathogen infection or to restrict pathogen growth. Mutations in the CaM binding proteins can lead to severe effects on the defense response of the plants towards pathogen infections. Cyclic nucleotide-gated channels (CNGCs) are functional protein channels in the plasma membrane that have overlapping CaM binding sites transport divalent cations such as Ca<sup>2+</sup>. However, the exact role of the positioning of the CNGCs in this pathway for plant defense is still unclear.

=== Abiotic stress response in plants ===
Change in intracellular Ca<sup>2+</sup> levels is used as a signature for diverse responses towards mechanical stimuli, osmotic and salt treatments, and cold and heat shocks. Different root cell types show a different Ca<sup>2+</sup> response to osmotic and salt stresses and this implies the cellular specificities of Ca<sup>2+</sup> patterns. In response to external stress CaM activates glutamate decarboxylase (GAD) that catalyzes the conversion of {{sc|L}}-glutamate to GABA. A tight control on the GABA synthesis is important for plant development and, hence, increased GABA levels can essentially affect plant development. Therefore, external stress can affect plant growth and development and CaM are involved in that pathway controlling this effect.{{citation needed|date=October 2017}}

===Plant examples===
====Sorghum====
The plant [[sorghum]] is well established model organism and can adapt in hot and dry environments. For this reason, it is used as a model to study calmodulin's role in plants.<ref name="Sanchez_2002" /> Sorghum contains seedlings that express a [[glycine]]-rich [[RNA-binding protein]], SbGRBP. This particular protein can be modulated by using heat as a stressor. Its unique location in the cell nucleus and cytosol demonstrates interaction with calmodulin that requires the use of Ca<sup>2+</sup>.<ref>{{cite journal | vauthors = Singh S, Virdi AS, Jaswal R, Chawla M, Kapoor S, Mohapatra SB, Manoj N, Pareek A, Kumar S, Singh P | display-authors = 6 | title = A temperature-responsive gene in sorghum encodes a glycine-rich protein that interacts with calmodulin | journal = Biochimie | volume = 137 | issue = Supplement C | pages = 115–123 | date = June 2017 | pmid = 28322928 | doi = 10.1016/j.biochi.2017.03.010 }}</ref> By exposing the plant to versatile [[stress (biology)|stress]] conditions, it can cause different [[proteins]] that enable the plant cells to tolerate environmental changes to become repressed. These modulated stress proteins are shown to interact with CaM. The ''CaMBP'' genes [[Gene expression|expressed]] in the sorghum are depicted as a “model crop” for researching the tolerance to heat and [[drought stress]].

====''Arabidopsis''====
In an ''Arabidopsis thaliana'' study, hundreds of different proteins demonstrated the possibility to bind to CaM in plants.<ref name="Sanchez_2002">{{cite journal | vauthors = Sanchez AC, Subudhi PK, Rosenow DT, Nguyen HT | s2cid = 25834614 | title = Mapping QTLs associated with drought resistance in sorghum (Sorghum bicolor L. Moench) | journal = Plant Molecular Biology | volume = 48 | issue = 5–6 | pages = 713–26 | date = 2002 | pmid = 11999845 | doi = 10.1023/a:1014894130270 }}</ref>

==Family members==
* [[Calmodulin 1]] ({{Gene|CALM1}})
* [[CALM2|Calmodulin 2]] ({{Gene|CALM2}})
* [[CALM3|Calmodulin 3]] ({{Gene|CALM3}})
* [[CALM1P1|calmodulin 1 pseudogene 1]] ({{Gene|CALM1P1}})
* [[CALML3|Calmodulin-like 3]] ({{Gene|CALML3}})
* [[CALML4|Calmodulin-like 4]] ({{Gene|CALML4}})
* [[CALML5|Calmodulin-like 5]] ({{Gene|CALML5}})
* [[CALML6|Calmodulin-like 6]] ({{Gene|CALML6}})

== Other calcium-binding proteins ==
Calmodulin belongs to one of the two main groups of calcium-binding proteins, called [[EF hand]] proteins. The other group, called [[annexin]]s, bind calcium and [[phospholipid]]s such as [[lipocortin]]. Many other proteins bind calcium, although binding calcium may not be considered their principal function in the cell.

== See also ==
*[[Protein kinase]]
*[[CAMK|Ca<sup>2+</sup>/calmodulin-dependent protein kinase]]

== References ==
{{reflist}}

== External links ==
* {{cite web | title = Myelin-associated Glycoprotein | url = http://www.pdb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb44_1.html | work = Molecule of the Month | date = July 2020 | publisher = RCSB PDB | access-date = 2021-06-19 | archive-date = 2010-05-29 | archive-url = https://web.archive.org/web/20100529084031/http://www.pdb.org/pdb/static.do?p=education_discussion%2Fmolecule_of_the_month%2Fpdb44_1.html | url-status = dead }}
* {{cite web | url = http://structbio.vanderbilt.edu/cabp_database/general/prot_pages/calmod.html | title = Home Page for Calmodulin | access-date = 2008-03-22 | vauthors = Nelson M, Chazin W | work =  EF-Hand Calcium-Binding Proteins Data Library | publisher = Vanderbilt University }}
* {{cite journal | url = http://calcium.uhnres.utoronto.ca/ctdb/ctdb/home.html | title = Calmodulin Target Database | access-date = 2008-03-22 | first = Mitsuhiko | last = Ikura | s2cid = 23097597 | journal = Journal of Structural and Functional Genomics | name-list-style = vanc | year = 2000 | volume = 1 | issue = 1 | publisher = Ontario Cancer Institute, University of Toronto | pages = 8–14 | doi = 10.1023/a:1011320027914 | pmid = 12836676 | archive-date = 2011-09-27 | archive-url = https://web.archive.org/web/20110927044015/http://calcium.uhnres.utoronto.ca/ctdb/ctdb/home.html | url-status = dead | url-access = subscription }}
* {{MeshName|Calmodulin}}
* {{InterPro|IPR015754}}
* Proteopedia page for [http://www.proteopedia.org/wiki/index.php/Calmodulin Calmodulin] and its [http://www.proteopedia.org/wiki/index.php/Calmodulin_in_motion conformational change]

{{Muscle tissue}}
{{Calcium-binding proteins}}
{{Nitric oxide signaling}}

[[Category:EF-hand-containing proteins]]
[[Category:Cell signaling]]
[[Category:Signal transduction]]
[[Category:Calcium signaling]]