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Protein

Calmodulin-2

Gene

CALM2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Calmodulin mediates the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding. Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases and phosphatases. Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis (PubMed:16760425). Mediates calcium-dependent inactivation of CACNA1C (PubMed:26969752). Positively regulates calcium-activated potassium channel activity of KCNN2 (PubMed:27165696).3 Publications

Miscellaneous

This protein has four functional calcium-binding sites.1 Publication

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Calcium bindingi21 – 3211 PublicationAdd BLAST12
Calcium bindingi57 – 6821 PublicationAdd BLAST12
Calcium bindingi94 – 10531 PublicationAdd BLAST12
Calcium bindingi130 – 14141 PublicationAdd BLAST12

GO - Molecular functioni

  • adenylate cyclase binding Source: CAFA
  • calcium channel inhibitor activity Source: UniProtKB
  • calcium ion binding Source: UniProtKB
  • disordered domain specific binding Source: CAFA
  • ion channel binding Source: BHF-UCL
  • protein kinase binding Source: BHF-UCL
  • protein phosphatase activator activity Source: BHF-UCL
  • protein serine/threonine kinase activator activity Source: BHF-UCL
  • titin binding Source: BHF-UCL

GO - Biological processi

  • detection of calcium ion Source: BHF-UCL
  • negative regulation of peptidyl-threonine phosphorylation Source: BHF-UCL
  • negative regulation of ryanodine-sensitive calcium-release channel activity Source: UniProtKB
  • positive regulation of cAMP biosynthetic process Source: CAFA
  • positive regulation of cyclic nucleotide metabolic process Source: BHF-UCL
  • positive regulation of cyclic-nucleotide phosphodiesterase activity Source: BHF-UCL
  • positive regulation of peptidyl-threonine phosphorylation Source: BHF-UCL
  • positive regulation of phosphoprotein phosphatase activity Source: BHF-UCL
  • positive regulation of protein autophosphorylation Source: BHF-UCL
  • positive regulation of protein dephosphorylation Source: BHF-UCL
  • positive regulation of protein serine/threonine kinase activity Source: BHF-UCL
  • positive regulation of ryanodine-sensitive calcium-release channel activity Source: BHF-UCL
  • regulation of cardiac muscle contraction Source: BHF-UCL
  • regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion Source: BHF-UCL
  • regulation of cell communication by electrical coupling involved in cardiac conduction Source: BHF-UCL
  • regulation of heart rate Source: BHF-UCL
  • regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum Source: BHF-UCL
  • response to calcium ion Source: BHF-UCL

Keywordsi

LigandCalcium, Metal-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Calmodulin-2Imported
Gene namesi
Name:CALM21 PublicationImported
Synonyms:CAM2, CAMB
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 2

Organism-specific databases

HGNCiHGNC:1445. CALM2.
MIMi114182. gene.
neXtProtiNX_P0DP24.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Cytoskeleton

Pathology & Biotechi

Involvement in diseasei

Long QT syndrome 15 (LQT15)6 Publications
The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM2 are the cause of LQT15.
Disease descriptionA form of long QT syndrome, a heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy.
See also OMIM:616249
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07327696D → V in LQT15; reduction in calcium affinity; highly decreased calcium-dependent inactivation of L-type calcium channel; increased action potential duration; not changed protein abundance; not changed structure; increased thermal stability in absence of calcium; decreased thermal stability in presence of calcium; significantly increased RYR2 interaction; increased ryanodine-sensitive calcium-release channel activity; decreased of KCNN2 calcium-activated potassium channel activity; not changed KCNN2 expression; not changed KCNN2 location at membrane. 4 PublicationsCorresponds to variant dbSNP:rs730882254Ensembl.1
Natural variantiVAR_07327798N → I in LQT15; reduction in calcium affinity. 1 PublicationCorresponds to variant dbSNP:rs398124647Ensembl.1
Natural variantiVAR_07854398N → S in LQT15; the mutant has significantly reduced calcium affinity compared to wild-type; calmodulin-RYR2 interaction is defective at low intracellular Ca(2+) concentrations and restored at moderate to high Ca(2+) concentrations; increased RYR2 calcium-release channel activity; decreased calcium-dependent inactivation of L-type calcium channel; not changed protein abundance; not changed structure; significantly reduced ryanodine-sensitive calcium-release channel activity; decreased of KCNN2 calcium-activated potassium channel activity; not changed KCNN2 expression; not changed KCNN2 location at membrane. 4 PublicationsCorresponds to variant dbSNP:rs398124647Ensembl.1
Natural variantiVAR_078544130D → G in LQT15; reduction in calcium affinity; not changed protein abundance; not changed structure; significantly decreased thermal stability in presence of clacium; significantly decreased RYR2 interaction; increased ryanodine-sensitive calcium-release channel activity; decreased of KCNN2 calcium-activated potassium channel activity; not changed KCNN2 expression; not changed KCNN2 location at membrane. 4 PublicationsCorresponds to variant dbSNP:rs730882252Ensembl.1
Natural variantiVAR_078262130D → V in LQT15. 1 Publication1
Natural variantiVAR_073279132D → E in LQT15; reduction in calcium affinity. 1 PublicationCorresponds to variant dbSNP:rs398124648Ensembl.1
Natural variantiVAR_073280134D → H in LQT15; reduction in calcium affinity. 1 PublicationCorresponds to variant dbSNP:rs398124650Ensembl.1
Natural variantiVAR_073281136Q → P in LQT15; reduction in calcium affinity. 1 PublicationCorresponds to variant dbSNP:rs398124649Ensembl.1

Keywords - Diseasei

Disease mutation, Long QT syndrome

Organism-specific databases

MIMi616249. phenotype.
OpenTargetsiENSG00000143933.
ENSG00000160014.
ENSG00000198668.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedCombined sources2 Publications
ChainiPRO_00004399332 – 149Calmodulin-2Add BLAST148

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylalanineCombined sources2 Publications1
Modified residuei22N6-acetyllysine; alternateCombined sources1
Cross-linki22Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2); alternateCombined sources
Cross-linki22Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); alternateBy similarity
Modified residuei45Phosphothreonine; by CaMK4By similarity1
Modified residuei82PhosphoserineCombined sources1
Modified residuei95N6-acetyllysineCombined sources1
Modified residuei100PhosphotyrosineCombined sources1
Modified residuei102PhosphoserineCombined sources1
Modified residuei111PhosphothreonineCombined sources1
Modified residuei116N6,N6,N6-trimethyllysine; alternateCombined sources1 Publication1
Modified residuei116N6-methyllysine; alternateCombined sources1
Modified residuei139PhosphotyrosineCombined sources1

Post-translational modificationi

Ubiquitination results in a strongly decreased activity.By similarity
Phosphorylation results in a decreased activity.By similarity

Keywords - PTMi

Acetylation, Isopeptide bond, Methylation, Phosphoprotein, Ubl conjugation

PTM databases

iPTMnetiP0DP24.

Expressioni

Gene expression databases

ExpressionAtlasiP0DP24. baseline and differential.

Organism-specific databases

HPAiHPA044999.

Interactioni

Subunit structurei

Interacts with MYO1C, MYO5A and RRAD. Interacts with MYO10 (By similarity). Interacts with CEP97, CCP110, TTN/titin and SRY (PubMed:9804419, PubMed:12871148, PubMed:15746192, PubMed:16760425, PubMed:17719545). Interacts with USP6; the interaction is calcium dependent (PubMed:16127172). Interacts with CDK5RAP2 (PubMed:20466722). Interacts with SCN5A (By similarity). Interacts with RYR1 (PubMed:18650434). Interacts with FCHO1 (PubMed:22484487). Interacts with MIP in a 1:2 stoichiometry; the interaction with the cytoplasmic domains from two MIP subunits promotes MIP water channel closure (By similarity). Interacts with ORAI1; this may play a role in the regulation of ORAI1-mediated calcium transport (By similarity). Interacts with IQCF1 (By similarity). Interacts with SYT7 (By similarity). Interacts with CEACAM1 (via cytoplasmic domain); this interaction is in a calcium dependent manner and reduces homophilic cell adhesion through dissociation of dimer (By similarity). Interacts with RYR2; regulates RYR2 calcium-release channel activity (PubMed:27516456, PubMed:18650434, PubMed:26164367). Interacts with PCP4; regulates calmodulin calcium-binding (PubMed:27876793). Interacts with the heterotetrameric KCNQ2 and KCNQ3 channel; the interaction is calcium-independent, constitutive and participates to the proper assembly of a functional heterotetrameric M channel (PubMed:27564677).By similarity14 Publications

GO - Molecular functioni

  • adenylate cyclase binding Source: CAFA
  • disordered domain specific binding Source: CAFA
  • ion channel binding Source: BHF-UCL
  • protein kinase binding Source: BHF-UCL
  • titin binding Source: BHF-UCL

Structurei

Secondary structure

1149
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi7 – 20Combined sources14
Beta strandi25 – 28Combined sources4
Helixi30 – 38Combined sources9
Turni39 – 41Combined sources3
Helixi46 – 54Combined sources9
Beta strandi61 – 64Combined sources4
Helixi66 – 75Combined sources10

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3O77X-ray2.35A45-149[»]
3O78X-ray2.60A/B45-149[»]
5COCX-ray2.67A10-78[»]
5J03X-ray2.00B1-149[»]
5NINX-ray1.70A/B1-149[»]
5VMSelectron microscopy3.70B1-149[»]
5WSUX-ray3.00A/B2-149[»]
5WSVX-ray2.33A/C1-147[»]
SMRiP0DP24.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini8 – 43EF-hand 1PROSITE-ProRule annotationAdd BLAST36
Domaini44 – 79EF-hand 2PROSITE-ProRule annotationAdd BLAST36
Domaini81 – 116EF-hand 3PROSITE-ProRule annotationAdd BLAST36
Domaini117 – 149EF-hand 4PROSITE-ProRule annotationAdd BLAST33

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni77 – 149Necessary and sufficient for interaction with PCP41 PublicationAdd BLAST73

Sequence similaritiesi

Belongs to the calmodulin family.Curated

Keywords - Domaini

Repeat

Phylogenomic databases

KOiK02183.

Family and domain databases

CDDicd00051. EFh. 2 hits.
InterProiView protein in InterPro
IPR011992. EF-hand-dom_pair.
IPR018247. EF_Hand_1_Ca_BS.
IPR002048. EF_hand_dom.
PfamiView protein in Pfam
PF13499. EF-hand_7. 2 hits.
SMARTiView protein in SMART
SM00054. EFh. 4 hits.
SUPFAMiSSF47473. SSF47473. 1 hit.
PROSITEiView protein in PROSITE
PS00018. EF_HAND_1. 4 hits.
PS50222. EF_HAND_2. 4 hits.

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P0DP24-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MADQLTEEQI AEFKEAFSLF DKDGDGTITT KELGTVMRSL GQNPTEAELQ
60 70 80 90 100
DMINEVDADG NGTIDFPEFL TMMARKMKDT DSEEEIREAF RVFDKDGNGY
110 120 130 140
ISAAELRHVM TNLGEKLTDE EVDEMIREAD IDGDGQVNYE EFVQMMTAK
Length:149
Mass (Da):16,838
Last modified:May 10, 2017 - v1
Checksum:i6B4BC3FCDE10727B
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti124E → Q in AAH08437 (PubMed:15489334).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07327696D → V in LQT15; reduction in calcium affinity; highly decreased calcium-dependent inactivation of L-type calcium channel; increased action potential duration; not changed protein abundance; not changed structure; increased thermal stability in absence of calcium; decreased thermal stability in presence of calcium; significantly increased RYR2 interaction; increased ryanodine-sensitive calcium-release channel activity; decreased of KCNN2 calcium-activated potassium channel activity; not changed KCNN2 expression; not changed KCNN2 location at membrane. 4 PublicationsCorresponds to variant dbSNP:rs730882254Ensembl.1
Natural variantiVAR_07327798N → I in LQT15; reduction in calcium affinity. 1 PublicationCorresponds to variant dbSNP:rs398124647Ensembl.1
Natural variantiVAR_07854398N → S in LQT15; the mutant has significantly reduced calcium affinity compared to wild-type; calmodulin-RYR2 interaction is defective at low intracellular Ca(2+) concentrations and restored at moderate to high Ca(2+) concentrations; increased RYR2 calcium-release channel activity; decreased calcium-dependent inactivation of L-type calcium channel; not changed protein abundance; not changed structure; significantly reduced ryanodine-sensitive calcium-release channel activity; decreased of KCNN2 calcium-activated potassium channel activity; not changed KCNN2 expression; not changed KCNN2 location at membrane. 4 PublicationsCorresponds to variant dbSNP:rs398124647Ensembl.1
Natural variantiVAR_078544130D → G in LQT15; reduction in calcium affinity; not changed protein abundance; not changed structure; significantly decreased thermal stability in presence of clacium; significantly decreased RYR2 interaction; increased ryanodine-sensitive calcium-release channel activity; decreased of KCNN2 calcium-activated potassium channel activity; not changed KCNN2 expression; not changed KCNN2 location at membrane. 4 PublicationsCorresponds to variant dbSNP:rs730882252Ensembl.1
Natural variantiVAR_078262130D → V in LQT15. 1 Publication1
Natural variantiVAR_073279132D → E in LQT15; reduction in calcium affinity. 1 PublicationCorresponds to variant dbSNP:rs398124648Ensembl.1
Natural variantiVAR_073280134D → H in LQT15; reduction in calcium affinity. 1 PublicationCorresponds to variant dbSNP:rs398124650Ensembl.1
Natural variantiVAR_073281136Q → P in LQT15; reduction in calcium affinity. 1 PublicationCorresponds to variant dbSNP:rs398124649Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M19311 mRNA. Translation: AAA35641.1.
D45887 mRNA. Translation: BAA08302.1.
U94728, U94725, U94726 Genomic DNA. Translation: AAC83174.1.
BT009916 mRNA. Translation: AAP88918.1.
CR541990 mRNA. Translation: CAG46787.1.
CR542021 mRNA. Translation: CAG46818.1.
AC073283 Genomic DNA. Translation: AAY24085.1.
BC003354 mRNA. Translation: AAH03354.1.
BC006464 mRNA. Translation: AAH06464.1.
BC008437 mRNA. Translation: AAH08437.1.
BC017385 mRNA. Translation: AAH17385.1.
BC018677 mRNA. Translation: AAH18677.1.
BC026065 mRNA. Translation: AAH26065.1.
CCDSiCCDS1832.1.
RefSeqiNP_001292553.1. NM_001305624.1.
NP_001292554.1. NM_001305625.1.
NP_001292555.1. NM_001305626.1.
NP_001316851.1. NM_001329922.1.
NP_001734.1. NM_001743.5.
NP_005175.2. NM_005184.3.
NP_008819.1. NM_006888.4.
UniGeneiHs.282410.
Hs.468442.
Hs.515487.

Genome annotation databases

EnsembliENST00000272298; ENSP00000272298; ENSG00000143933.
GeneIDi801.
805.
808.
KEGGihsa:801.
hsa:805.
hsa:808.

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiCALM2_HUMAN
AccessioniPrimary (citable) accession number: P0DP24
Secondary accession number(s): P02593
, P62158, P70667, P99014, Q13942, Q53S29, Q61379, Q61380, Q96HK3
Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 10, 2017
Last sequence update: May 10, 2017
Last modified: January 31, 2018
This is version 9 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 2
    Human chromosome 2: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families