Calmodulin 1

CALM1
Available structures PDB Human UniProt search: PDBe RCSB List of PDB id codes 2VAY, 1Y6W, 4JPZ, 3UCY, 1WRZ, 4G28, 1ZOT, 1YRT, 1IQ5, 1CDL, 2LL6, 3HR4, 4BW7, 4BW8, 1YR5, 4J9Y, 4LZX, 1L7Z, 1ZUZ, 2BE6, 2V01, 1XFV, 2M55, 1CTR, 2I08, 2MG5, 2R28, 3O77, 4UPU, 2L7L, 2K0F, 2M0K, 4V0C, 1SW8, 2WEL, 3DVK, 2M0J, 3DVM, 2KUH, 1K90, 1K93, 4G27, 1CLL, 2KUG, 1XFX, 4DJC, 2LQC, 2LQP, 4L79, 2W73, 2LV6, 1NKF, 2JZI, 3UCT, 4GOW, 1J7O, 1PK0, 4Q5U, 2V02, 3BYA, 4Q57, 2KNE, 1YRU, 2Y4V, 2L53, 2F3Y, 3O78, 1LVC, 4M1L, 2K0E, 1S26, 4DCK, 1XFW, 3SUI, 2X0G, 3EWV, 1XFY, 2LL7, 4OVN, 3J41, 2BKI, 1SK6, 3DVJ, 3UCW, 2LGF, 4UMO, 3DVE, 4JQ0, 3OXQ, 2K61, 1XFU, 3SJQ, 2K0J, 4BYF, 1J7P, 3G43, 3EWT, 4J9Z, 1XFZ, 2F3Z, 1IWQ, 2N6A, 2HF5, 2N27, 4ZLK, 5COC
Identifiers
Aliases	CALM1, CALML2, CAMI, CPVT4, DD132, PHKD, caM, LQT14, Calmodulin 1, calmodulin 1 (phosphorylase kinase, delta), CAMC, CAMB, CAMIII, CAM3, CAM2
External IDs	OMIM: 114180; HomoloGene: 134804; GeneCards: CALM1; OMA:CALM1 - orthologs
Gene location (Human) Chr. Chromosome 14 (human)[1] Band 14q32.11 Start 90,396,502 bp[1] End 90,408,268 bp[1]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in lateral nuclear group of thalamus internal globus pallidus Parietal Lobe postcentral gyrus Pons frontal pole orbitofrontal cortex superior vestibular nucleus paraflocculus of cerebellum external globus pallidus n/a More reference expression data BioGPS n/a
Gene ontology Molecular function calcium ion binding protein binding calcium channel inhibitor activity protein kinase binding titin binding protein serine/threonine kinase activator activity transmembrane transporter binding metal ion binding protein phosphatase activator activity adenylate cyclase binding disordered domain specific binding inositol-1,4,5-trisphosphate 3-kinase activity ligand-gated ion channel activity adenylate cyclase activator activity protein domain specific binding nitric-oxide synthase regulator activity type 3 metabotropic glutamate receptor binding N-terminal myristoylation domain binding phosphatidylinositol 3-kinase binding protein N-terminus binding calcium-dependent protein binding nitric-oxide synthase binding Cellular component cytoplasm cytosol calcium channel complex extracellular region spindle microtubule neuron projection cytoskeleton nucleus centrosome voltage-gated potassium channel complex extracellular exosome spindle pole growth cone plasma membrane spindle sarcomere nucleoplasm vesicle postsynaptic density catalytic complex microtubule organizing center synaptic vesicle membrane mitochondrial membranes protein-containing complex myelin sheath Biological process muscle contraction response to amphetamine positive regulation of protein serine/threonine kinase activity detection of calcium ion Fc-epsilon receptor signaling pathway positive regulation of phosphoprotein phosphatase activity G2/M transition of mitotic cell cycle regulation of high voltage-gated calcium channel activity positive regulation of DNA binding substantia nigra development positive regulation of protein dephosphorylation inositol phosphate metabolic process positive regulation of nitric-oxide synthase activity glycogen catabolic process positive regulation of cyclic-nucleotide phosphodiesterase activity G protein-coupled receptor signaling pathway regulation of cytokinesis regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion regulation of rhodopsin mediated signaling pathway response to corticosterone negative regulation of peptidyl-threonine phosphorylation activation of adenylate cyclase activity regulation of heart rate positive regulation of ryanodine-sensitive calcium-release channel activity response to calcium ion regulation of ryanodine-sensitive calcium-release channel activity regulation of nitric-oxide synthase activity platelet degranulation negative regulation of ryanodine-sensitive calcium-release channel activity MAPK cascade positive regulation of peptidyl-threonine phosphorylation positive regulation of protein autophosphorylation regulation of cardiac muscle contraction regulation of cell communication by electrical coupling involved in cardiac conduction regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum calcium-mediated signaling ion transmembrane transport Wnt signaling pathway, calcium modulating pathway positive regulation of GTPase activity protein methylation establishment of protein localization to membrane establishment of protein localization to mitochondrial membrane regulation of synaptic vesicle endocytosis regulation of synaptic vesicle exocytosis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 801 n/a Ensembl ENSG00000198668 n/a UniProt P0DP23 P0DP24 n/a RefSeq (mRNA) NM_001166106 NM_006888 NM_001363669 NM_001363670 n/a RefSeq (protein) NP_001292553 NP_001292554 NP_001292555 NP_001734 NP_001316850 NP_001316851 NP_001316852 NP_001316853 NP_001316854 NP_001316855 NP_005175 NP_008819 NP_001350598 NP_001350599 NP_008819 NP_001292553 NP_001292554 NP_001292555 NP_001734 NP_001316850 NP_001316851 NP_001316852 NP_001316853 NP_001316854 NP_001316855 NP_005175 n/a Location (UCSC) Chr 14: 90.4 – 90.41 Mb n/a PubMed search [2] n/a
Wikidata
View/Edit Human

Calmodulin 1 is a protein in humans that is encoded by the CALM1 gene.[3]

Calmodulin[4] plays a role in calcium signal transduction pathways by regulating control of ion channels, enzymes, aquaporins, and other proteins. It functions as a calcium-binding protein that has been grouped into the EF-hand motif found in eukaryotic cells. Calmodulin plays a significant role in numerous cellular pathways and it acts as a calcium detector within the cells that interact with varied target proteins. Additionally, it simulates[5] the activation of over twenty amino acids which helps to control various physiological functions. It is also required for various regulatory roles in cell proliferation and throughout many points during the cell cycle.

Upon binding to targeted calcium (acts as ligand), calmodulin undergoes a change in shape that allows it to interact with multiple protein types including phosphatases, ion channels, and kinases. This conformational change is associated with undergoing various cellular processes: including muscle contraction, release of neurotransmitters into the bloodstream, and gene expression.

Function

Calmodulin 1 is the archetype of the family of calcium-modulated (calmodulin) proteins of which nearly 20 members have been found. They are identified by their occurrence in the cytosol or on membranes facing the cytosol and by a high affinity for calcium. Calmodulin contains 149 amino acids and has 4 calcium-binding EF hand motifs. Its functions include roles in growth and the cell cycle as well as in signal transduction and the synthesis and release of neurotransmitters.[6]

Gene expression

In humans, there are three genetic isoforms of calmodulin which are encoded by the homologous gene variations: CALM1, CALM2, and CALM3. Each three of the isoforms produce distinct, yet closely associated forms of calmodulin. At the nucleic acid level, the coding regions differ by a 15% between CALM1 and CALM2 and 13% between CALM2 and CALM3.[7]

Calmodulin I, abbreviated CALM1, is located on chromosome 14 of the human genome, and is one of the three isoforms of calmodulin. It’s found in all human tissues, although the expression varies depending on tissue type. There are high expression levels found in the brain, muscle, and blood.

Throughout the body, CALM1 plays a significant role in muscle contraction and relaxation in skeletal and smooth muscle. In heart muscle, CALM1 is vital for the regulation of calcium signaling to control efficient cardiac functioning. Calcium/calmodulin protein kinases (CaMKs)[8] work symbiotically to regulate calcium signaling throughout the body. CAMKII, the most prolific isoform, is found in cardiac tissue where it controls excitation-contraction coupling. Calmodulin I also plays an important role in the immune system through lymphocytes (white blood cells) where it contributes to immune cell function and activation. In bone tissue, Calmodulin I is associated with osteoblasts, osteoclasts, and osteocytes, by functioning in intracellular calcium signaling to ensure bone mineralization, resorption, and remodeling.

Calmodulin 1[7] can be expressed as one of two transcript types, which can be distinguished by length and tissue location. The major transcript is present in all tissues and is recorded as 1.7-kb in length. The minor transcript is either 4.1-kb or 4.4kb in length, and is only found in brain and skeletal muscle tissue. The difference in transcript lengths are caused by substitute cleavage and polyadenylation signals (APA), which permits the origination of different mRNA isoforms.

Pseudogenes

There are two known pseudogenes of Calmodulin 1, which are known as CALMIPI and CALMIP2. CALMPI was first discovered on chromosome 7, and the CALMPI2 was later identified on chromosome X. Experimentation shows both pseudogenes lack introns and have multiple mutations in their open reading frame, meaning that they cease all functions.

Mapping

Human[9] and rodent hybridized somatic cell panels show that complementary DNA for calmodulin I was localized to chromosome 14, with some cross hybridization activity on chromosome 7, and minor involvement on chromosome X.

Identifiers

• Protein Identification: P62158 (aka CALM_HUMAN)
• Gene Identification: 114180

CALM1 Biochemical & Signaling Pathways[10] Kyoto Encyclopedia of Genes and Genomes (KEGG):[11]
hsa04020	Calcium signaling pathway
hsa04070	Phosphatidylinositol signaling system
hsa04114	Oocyte meiosis
hsa04270	Vascular smooth muscle contraction
hsa04720	Long-term potentiation
hsa04722	Neurotrophin signaling pathway
hsa04740	Olfactory transduction
hsa04744	Phototransduction
hsa04910	Insulin signaling pathway
hsa04912	GnRH signaling pathway
hsa04916	Melanogenesi
hsa05010	Alzheimer's disease
hsa05214	Glioma

Calmodulin I protein family domains:
PF00036	EF hand
PF08726	Ca2+ insensitive EF hand
PF12763	Cytoskeletal-regulatory complex EF hand
PF13202	EF hand
PF13405	EF-hand domain
PF13499	EF-hand domain pair
PF13833	EF-hand domain pair
PF14658	EF-hand domain

Interactions

Calmodulin 1 has been shown to interact with:

• AKAP9,[12]
• Androgen receptor,[13]
• IQGAP1,[14][15]
• PPEF1,[16] and
• TRPV1.[17]

Mutations

Mutations of CALM1 CALM2 or CALM3 can lead to critical cardiac deficiencies including long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT).[18] Studies investigating calmodulin-associated diseases have discovered multiple proteins modified by calmodulin that determine the virulence of the mutations, including the cardiac L-type calcium channel (LTCC) Cav1.2, the sarcoplasmic reticulum calcium release channel, and the ryanodine receptor 2 (RyR2).

CALM1 disease mutations are often diagnosed in patients aged ten or younger, whereas CALM2 and CALM3 mutations typically develop in adulthood. Calmodulin functioning defects cause interference of vital calcium signaling events within the heart muscle which disrupts membrane ion channels. The disruptions in cell signaling can lead to potentially life-threatening cardiac disturbances in adolescence.

Diseases correlated with CALM1

• Long QT Syndrome-14 (LQT14)

LQT14[19] is caused by the heterozygous mutation in the CALM1 gene (114180) on chromosome 14q32. It often produces life-threatening ventricular arrhythmias that manifest at a young age with persistent periods of T-wave alternans, notably sustained QTc intervals, and irregular 2:1 atrioventricular blocks.

• Catecholaminergic polymorphic ventricular tachycardia (CPVT)

CPVT[20] is an inherited disorder that presents with episodes of syncope and/or sudden cardiac infarctions during exercise or extreme emotional episodes in humans without structural cardiac deformities. Mutations in the ryanodine-receptor 2 channel (RYR2) that causes calcium leakage from the sarcoplasmic reticulum have been proven to cause about half of dominantly inherited cases of CPVT.  

It has been discovered that some individuals with CPVT have distinct mutations on the Calmodulin I gene. The mutations cause disruption in the proper functioning of the gene, which leads to abnormal calcium control in cardiac tissue cells. The calcium disturbance can trigger ventricular arrhythmias in reaction to blood vessel vasoconstriction, such as during periods of exercise or elevated stress.  

References

1. GRCh38: Ensembl release 89: ENSG00000198668 – Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. Wawrzynczak EJ, Perham RN (August 1984). "Isolation and nucleotide sequence of a cDNA encoding human calmodulin". Biochemistry International. 9 (2): 177–185. PMID 6385987.
4. "UniProt". www.uniprot.org. Retrieved 2023-10-11.
5. Means AR, VanBerkum MF, Bagchi I, Lu KP, Rasmussen CD (1991). "Regulatory functions of calmodulin". Pharmacology & Therapeutics. 50 (2): 255–270. doi:10.1016/0163-7258(91)90017-g. PMID 1763137.
6. "Entrez Gene: CALM1 calmodulin 1 (phosphorylase kinase, delta)".
7. Hasterok S, Nyesiga B, Wingren AG (25 February 2022). "Calm-1". atlasgeneticsoncology.org. Retrieved 2023-10-11.
8. Junho CV, Caio-Silva W, Trentin-Sonoda M, Carneiro-Ramos MS (2020). "An Overview of the Role of Calcium/Calmodulin-Dependent Protein Kinase in Cardiorenal Syndrome". Frontiers in Physiology. 11: 735. doi:10.3389/fphys.2020.00735. PMC 7372084. PMID 32760284.
9. "Entry - *114180 - CALMODULIN 1; CALM1 - OMIM". www.omim.org. Retrieved 2023-10-11.
10. "Human Gene CALM1 (uc001xyl.2)". genome.ucsc.edu. Retrieved 2023-11-02.
11. "KEGG: Kyoto Encyclopedia of Genes and Genomes". www.genome.jp. Retrieved 2023-10-26.
12. Takahashi M, Yamagiwa A, Nishimura T, Mukai H, Ono Y (September 2002). "Centrosomal proteins CG-NAP and kendrin provide microtubule nucleation sites by anchoring gamma-tubulin ring complex". Molecular Biology of the Cell. 13 (9): 3235–3245. doi:10.1091/mbc.E02-02-0112. PMC 124155. PMID 12221128.
13. Cifuentes E, Mataraza JM, Yoshida BA, Menon M, Sacks DB, Barrack ER, Reddy GP (January 2004). "Physical and functional interaction of androgen receptor with calmodulin in prostate cancer cells". Proceedings of the National Academy of Sciences of the United States of America. 101 (2): 464–469. Bibcode:2004PNAS..101..464C. doi:10.1073/pnas.0307161101. PMC 327170. PMID 14695896.
14. Li Z, Sacks DB (February 2003). "Elucidation of the interaction of calmodulin with the IQ motifs of IQGAP1". The Journal of Biological Chemistry. 278 (6): 4347–4352. doi:10.1074/jbc.M208579200. PMID 12446675.
15. Briggs MW, Li Z, Sacks DB (March 2002). "IQGAP1-mediated stimulation of transcriptional co-activation by beta-catenin is modulated by calmodulin". The Journal of Biological Chemistry. 277 (9): 7453–7465. doi:10.1074/jbc.M104315200. PMID 11734550.
16. Kutuzov MA, Solov'eva OV, Andreeva AV, Bennett N (May 2002). "Protein Ser/Thr phosphatases PPEF interact with calmodulin". Biochemical and Biophysical Research Communications. 293 (3): 1047–1052. doi:10.1016/S0006-291X(02)00338-8. PMID 12051765.
17. Numazaki M, Tominaga T, Takeuchi K, Murayama N, Toyooka H, Tominaga M (June 2003). "Structural determinant of TRPV1 desensitization interacts with calmodulin". Proceedings of the National Academy of Sciences of the United States of America. 100 (13): 8002–8006. Bibcode:2003PNAS..100.8002N. doi:10.1073/pnas.1337252100. PMC 164702. PMID 12808128.
18. Hussey JW, Limpitikul WB, Dick IE (December 2023). "Calmodulin Mutations in Human Disease". Channels. 17 (1): 2165278. doi:10.1080/19336950.2023.2165278. PMC 9839377. PMID 36629534.
19. Crotti L, Spazzolini C, Tester DJ, Ghidoni A, Baruteau AE, Beckmann BM, et al. (September 2019). "Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry". European Heart Journal. 40 (35): 2964–2975. doi:10.1093/eurheartj/ehz311. PMC 6748747. PMID 31170290.
20. Nyegaard M, Overgaard MT, Søndergaard MT, Vranas M, Behr ER, Hildebrandt LL, et al. (October 2012). "Mutations in calmodulin cause ventricular tachycardia and sudden cardiac death". American Journal of Human Genetics. 91 (4): 703–712. doi:10.1016/j.ajhg.2012.08.015. PMC 3484646. PMID 23040497.

Further reading

• Zhang M, Yuan T (1999). "Molecular mechanisms of calmodulin's functional versatility". Biochemistry and Cell Biology. 76 (2–3): 313–323. doi:10.1139/bcb-76-2-3-313. PMID 9923700.
• Gusev NB (October 2001). "Some properties of caldesmon and calponin and the participation of these proteins in regulation of smooth muscle contraction and cytoskeleton formation". Biochemistry. Biokhimiia. 66 (10): 1112–1121. doi:10.1023/A:1012480829618. PMID 11736632. S2CID 310781.
• Benaim G, Villalobo A (August 2002). "Phosphorylation of calmodulin. Functional implications". European Journal of Biochemistry. 269 (15): 3619–3631. doi:10.1046/j.1432-1033.2002.03038.x. hdl:10261/79981. PMID 12153558.
• Trudeau MC, Zagotta WN (May 2003). "Calcium/calmodulin modulation of olfactory and rod cyclic nucleotide-gated ion channels". The Journal of Biological Chemistry. 278 (21): 18705–18708. doi:10.1074/jbc.R300001200. PMID 12626507.

External links

• UniProt.[1] Calm1 Human Gene

1. "CALM1 Gene", Definitions, Qeios, 2020-02-07, doi:10.32388/8gddrl, S2CID 243222152, retrieved 2023-10-16