Calmodulin 1

Last updated
CALM1
Protein CALM1 PDB 1a29.png
Available structures
PDB Human UniProt search: PDBe RCSB
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
Orthologs
SpeciesHumanMouse
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)

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

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:

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

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.

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.  

Related Research Articles

<span class="mw-page-title-main">Calmodulin</span> Messenger protein

Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca2+, and the binding of Ca2+ is required for the activation of calmodulin. Once bound to Ca2+, calmodulin acts as part of a calcium signal transduction pathway by modifying its interactions with various target proteins such as kinases or phosphatases.

<span class="mw-page-title-main">Nitric oxide synthase</span> Enzyme catalysing the formation of the gasotransmitter NO(nitric oxide)

Nitric oxide synthases (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and peristalsis, and is involved in angiogenesis and neural development. It may function as a retrograde neurotransmitter. Nitric oxide is mediated in mammals by the calcium-calmodulin controlled isoenzymes eNOS and nNOS. The inducible isoform, iNOS, involved in immune response, binds calmodulin at physiologically relevant concentrations, and produces NO as an immune defense mechanism, as NO is a free radical with an unpaired electron. It is the proximate cause of septic shock and may function in autoimmune disease.

<span class="mw-page-title-main">Romano–Ward syndrome</span> Medical condition

Romano–Ward syndrome is the most common form of congenital Long QT syndrome (LQTS), a genetic heart condition that affects the electrical properties of heart muscle cells. Those affected are at risk of abnormal heart rhythms which can lead to fainting, seizures, or sudden death. Romano–Ward syndrome can be distinguished clinically from other forms of inherited LQTS as it affects only the electrical properties of the heart, while other forms of LQTS can also affect other parts of the body.

<span class="mw-page-title-main">Andersen–Tawil syndrome</span> Rare autosomal dominant genetic disorder

Andersen–Tawil syndrome, also called Andersen syndrome and long QT syndrome 7, is a rare genetic disorder affecting several parts of the body. The three predominant features of Andersen–Tawil syndrome include disturbances of the electrical function of the heart characterised by an abnormality seen on an electrocardiogram and a tendency to abnormal heart rhythms, physical characteristics including low-set ears and a small lower jaw, and intermittent periods of muscle weakness known as hypokalaemic periodic paralysis.

Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (e.g., muscle, glial cells, neurons, etc.) with a permeability to the calcium ion Ca2+. These channels are slightly permeable to sodium ions, so they are also called Ca2+–Na+ channels, but their permeability to calcium is about 1000-fold greater than to sodium under normal physiological conditions.

<span class="mw-page-title-main">Telokin</span> Protein domain

Telokin is an abundant protein found in smooth-muscle. It is identical to the C-terminus of myosin light-chain kinase. Telokin may play a role in the stabilization of unphosphorylated smooth-muscle myosin filaments. Because of its origin as the C-terminal end of smooth muscle myosin light chain kinase, it is called "telokin".

<span class="mw-page-title-main">Desmoglein-2</span> Protein found in humans

Desmoglein-2 is a protein that in humans is encoded by the DSG2 gene. Desmoglein-2 is highly expressed in epithelial cells and cardiomyocytes. Desmoglein-2 is localized to desmosome structures at regions of cell-cell contact and functions to structurally adhere adjacent cells together. In cardiac muscle, these regions are specialized regions known as intercalated discs. Mutations in desmoglein-2 have been associated with arrhythmogenic right ventricular cardiomyopathy and familial dilated cardiomyopathy.

<span class="mw-page-title-main">Calsequestrin</span> Calcium-binding protein

Calsequestrin is a calcium-binding protein that acts as a calcium buffer within the sarcoplasmic reticulum. The protein helps hold calcium in the cisterna of the sarcoplasmic reticulum after a muscle contraction, even though the concentration of calcium in the sarcoplasmic reticulum is much higher than in the cytosol. It also helps the sarcoplasmic reticulum store an extraordinarily high amount of calcium ions. Each molecule of calsequestrin can bind 18 to 50 Ca2+ ions. Sequence analysis has suggested that calcium is not bound in distinct pockets via EF-hand motifs, but rather via presentation of a charged protein surface. Two forms of calsequestrin have been identified. The cardiac form Calsequestrin-2 (CASQ2) is present in cardiac and slow skeletal muscle and the fast skeletal form Calsequestrin-1(CASQ1) is found in fast skeletal muscle. The release of calsequestrin-bound calcium (through a calcium release channel) triggers muscle contraction. The active protein is not highly structured, more than 50% of it adopting a random coil conformation. When calcium binds there is a structural change whereby the alpha-helical content of the protein increases from 3 to 11%. Both forms of calsequestrin are phosphorylated by casein kinase 2, but the cardiac form is phosphorylated more rapidly and to a higher degree. Calsequestrin is also secreted in the gut where it deprives bacteria of calcium ions..

<span class="mw-page-title-main">Catecholaminergic polymorphic ventricular tachycardia</span> Medical condition

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited genetic disorder that predisposes those affected to potentially life-threatening abnormal heart rhythms or arrhythmias. The arrhythmias seen in CPVT typically occur during exercise or at times of emotional stress, and classically take the form of bidirectional ventricular tachycardia or ventricular fibrillation. Those affected may be asymptomatic, but they may also experience blackouts or even sudden cardiac death.

<span class="mw-page-title-main">PRKACA</span> Protein-coding gene in the species Homo sapiens

The catalytic subunit α of protein kinase A is a key regulatory enzyme that in humans is encoded by the PRKACA gene. This enzyme is responsible for phosphorylating other proteins and substrates, changing their activity. Protein kinase A catalytic subunit is a member of the AGC kinase family, and contributes to the control of cellular processes that include glucose metabolism, cell division, and contextual memory. PKA Cα is part of a larger protein complex that is responsible for controlling when and where proteins are phosphorylated. Defective regulation of PKA holoenzyme activity has been linked to the progression of cardiovascular disease, certain endocrine disorders and cancers.

<span class="mw-page-title-main">Ryanodine receptor 2</span> Transport protein and coding gene in humans

Ryanodine receptor 2 (RYR2) is one of a class of ryanodine receptors and a protein found primarily in cardiac muscle. In humans, it is encoded by the RYR2 gene. In the process of cardiac calcium-induced calcium release, RYR2 is the major mediator for sarcoplasmic release of stored calcium ions.

<span class="mw-page-title-main">CALM3</span> Protein-coding gene in the species Homo sapiens

Calmodulin 3 is a protein that in humans is encoded by the CALM3 gene.

<span class="mw-page-title-main">CALM2</span> Protein-coding gene in the species Homo sapiens

Calmodulin 2 is a protein that in humans is encoded by the CALM2 gene. A member of the calmodulin family of signaling molecules, it is an intermediary between calcium ions, which act as a second messenger, and many intracellular processes, such as the contraction of cardiac muscle.

<span class="mw-page-title-main">CAMK2G</span> Protein-coding gene in the species Homo sapiens

Calcium/calmodulin-dependent protein kinase type II gamma chain is an enzyme that in humans is encoded by the CAMK2G gene.

<span class="mw-page-title-main">S100-A1</span> Protein-coding gene in the species Homo sapiens

Protein S100-A1, also known as S100 calcium-binding protein A1 is a protein which in humans is encoded by the S100A1 gene. S100A1 is highly expressed in cardiac and skeletal muscle, and localizes to Z-discs and sarcoplasmic reticulum. S100A1 has shown promise as an effective candidate for gene therapy to treat post-myocardially infarcted cardiac tissue.

<span class="mw-page-title-main">MYL2</span> Protein-coding gene in the species Homo sapiens

Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MLC-2) also known as the regulatory light chain of myosin (RLC) is a protein that in humans is encoded by the MYL2 gene. This cardiac ventricular RLC isoform is distinct from that expressed in skeletal muscle (MYLPF), smooth muscle (MYL12B) and cardiac atrial muscle (MYL7).

<span class="mw-page-title-main">Triadin</span> Protein-coding gene in humans

Triadin, also known as TRDN, is a human gene associated with the release of calcium ions from the sarcoplasmic reticulum triggering muscular contraction through calcium-induced calcium release. Triadin is a multiprotein family, arising from different processing of the TRDN gene on chromosome 6. It is a transmembrane protein on the sarcoplasmic reticulum due to a well defined hydrophobic section and it forms a quaternary complex with the cardiac ryanodine receptor (RYR2), calsequestrin (CASQ2) and junctin proteins. The luminal (inner compartment of the sarcoplasmic reticulum) section of Triadin has areas of highly charged amino acid residues that act as luminal Ca2+ receptors. Triadin is also able to sense luminal Ca2+ concentrations by mediating interactions between RYR2 and CASQ2. Triadin has several different forms; Trisk 95 and Trisk 51, which are expressed in skeletal muscle, and Trisk 32 (CT1), which is mainly expressed in cardiac muscle.

<span class="mw-page-title-main">Phosphorylase kinase, alpha 1</span> Protein-coding gene in the species Homo sapiens

Phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform is an enzyme that in humans is encoded by the PHKA1 gene. It is the muscle isoform of Phosphorylase kinase (PhK).

<span class="mw-page-title-main">MYLK</span> Gene of the immunoglobulin superfamily

Myosin light chain kinase, smooth muscle also known as kinase-related protein (KRP) or telokin is an enzyme that in humans is encoded by the MYLK gene.

Calcium buffering describes the processes which help stabilise the concentration of free calcium ions within cells, in a similar manner to how pH buffers maintain a stable concentration of hydrogen ions. The majority of calcium ions within the cell are bound to intracellular proteins, leaving a minority freely dissociated. When calcium is added to or removed from the cytoplasm by transport across the cell membrane or sarcoplasmic reticulum, calcium buffers minimise the effect on changes in cytoplasmic free calcium concentration by binding calcium to or releasing calcium from intracellular proteins. As a result, 99% of the calcium added to the cytosol of a cardiomyocyte during each cardiac cycle becomes bound to calcium buffers, creating a relatively small change in free calcium.

References

  1. 1 2 3 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. 1 2 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

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