Calmodulin 1
{{Short description|Protein found in humans}}
{{Infobox_gene}}
Calmodulin 1 is a protein in humans that is encoded by the CALM1 gene.{{cite journal | vauthors = Wawrzynczak EJ, Perham RN | title = Isolation and nucleotide sequence of a cDNA encoding human calmodulin | journal = Biochemistry International | volume = 9 | issue = 2 | pages = 177–185 | date = August 1984 | pmid = 6385987 }}
Calmodulin{{Cite web |title=UniProt |url=https://www.uniprot.org/uniprotkb/P0DP23/entry |access-date=2023-10-11 |website=www.uniprot.org}} 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{{cite journal | vauthors = Means AR, VanBerkum MF, Bagchi I, Lu KP, Rasmussen CD | title = Regulatory functions of calmodulin | journal = Pharmacology & Therapeutics | volume = 50 | issue = 2 | pages = 255–270 | date = 1991 | pmid = 1763137 | doi = 10.1016/0163-7258(91)90017-g }} 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.{{cite web | title = Entrez Gene: CALM1 calmodulin 1 (phosphorylase kinase, delta)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=801}}
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.{{Cite web | title = Calm-1 | date = 25 February 2022 | vauthors = Hasterok S, Nyesiga B, Wingren AG |url=https://atlasgeneticsoncology.org/gene/208988/calm-1 |access-date=2023-10-11 |website=atlasgeneticsoncology.org |language=en}}
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){{cite journal | vauthors = Junho CV, Caio-Silva W, Trentin-Sonoda M, Carneiro-Ramos MS | title = An Overview of the Role of Calcium/Calmodulin-Dependent Protein Kinase in Cardiorenal Syndrome | journal = Frontiers in Physiology | volume = 11 | pages = 735 | date = 2020 | pmid = 32760284 | pmc = 7372084 | doi = 10.3389/fphys.2020.00735 | doi-access = free }} 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 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{{Cite web |title=Entry - *114180 - CALMODULIN 1; CALM1 - OMIM |url=https://www.omim.org/entry/114180 |access-date=2023-10-11 |website=www.omim.org |language=en-us}} 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: [https://www.uniprot.org/uniprotkb/P62158/history P62158] (aka CALM_HUMAN)
- Gene Identification: [https://www.omim.org/entry/114180 114180]
class="wikitable"
|+ ! colspan="2" |CALM1 Biochemical & Signaling Pathways{{Cite web |title=Human Gene CALM1 (uc001xyl.2) |url=https://genome.ucsc.edu/cgi-bin/hgGene?hgsid=1741652964_xv0xOw0uY2R5Fq5UW02BHNUdiqaQ&hgg_section_pathways_close=1#pathways |access-date=2023-11-02 |website=genome.ucsc.edu}} Kyoto Encyclopedia of Genes and Genomes (KEGG):{{Cite web |title=KEGG: Kyoto Encyclopedia of Genes and Genomes |url=https://www.genome.jp/kegg/ |access-date=2023-10-26 |website=www.genome.jp}} |
[https://www.genome.jp/kegg-bin/show_pathway?hsa04070+801 hsa04020] |
[https://www.genome.jp/kegg-bin/show_pathway?hsa04070+801 hsa04070]
|Phosphatidylinositol signaling system |
[https://www.genome.jp/kegg-bin/show_pathway?hsa04114+801 hsa04114]
|Oocyte meiosis |
[https://www.genome.jp/kegg-bin/show_pathway?hsa04270+801 hsa04270]
|Vascular smooth muscle contraction |
[https://www.genome.jp/kegg-bin/show_pathway?hsa04720+801 hsa04720]
|Long-term potentiation |
[https://www.genome.jp/kegg-bin/show_pathway?hsa04722+801 hsa04722]
|Neurotrophin signaling pathway |
[https://www.genome.jp/kegg-bin/show_pathway?hsa04740+801 hsa04740]
|Olfactory transduction |
[https://www.genome.jp/kegg-bin/show_pathway?hsa04744+801 hsa04744] |
[https://www.genome.jp/kegg-bin/show_pathway?hsa04910+801 hsa04910] |
[https://www.genome.jp/kegg-bin/show_pathway?hsa04912+801 hsa04912]
|GnRH signaling pathway |
[https://www.genome.jp/kegg-bin/show_pathway?hsa04916+801 hsa04916] |
[https://www.genome.jp/kegg-bin/show_pathway?hsa05010+801 hsa05010] |
[https://www.genome.jp/kegg-bin/show_pathway?hsa05214+801 hsa05214] |
class="wikitable"
|+ ! colspan="2" |Calmodulin I protein family domains: |
[https://www.ebi.ac.uk/interpro/entry/pfam/PF00036/ PF00036] |
[https://www.ebi.ac.uk/interpro/entry/pfam/PF08726/ PF08726]
|Ca2+ insensitive EF hand |
[https://www.ebi.ac.uk/interpro/entry/pfam/PF12763/ PF12763]
|Cytoskeletal-regulatory complex EF hand |
[https://www.ebi.ac.uk/interpro/entry/pfam/PF13202/ PF13202]
|EF hand |
[https://www.ebi.ac.uk/interpro/entry/pfam/PF13405/ PF13405]
|EF-hand domain |
[https://www.ebi.ac.uk/interpro/entry/pfam/PF13499/ PF13499]
|EF-hand domain pair |
[https://www.ebi.ac.uk/interpro/entry/pfam/PF13833/ PF13833]
|EF-hand domain pair |
[https://www.ebi.ac.uk/interpro/entry/pfam/PF14658/ PF14658]
|EF-hand domain |
Interactions
Calmodulin 1 has been shown to interact with:
- AKAP9,{{cite journal | vauthors = Takahashi M, Yamagiwa A, Nishimura T, Mukai H, Ono Y | title = Centrosomal proteins CG-NAP and kendrin provide microtubule nucleation sites by anchoring gamma-tubulin ring complex | journal = Molecular Biology of the Cell | volume = 13 | issue = 9 | pages = 3235–3245 | date = September 2002 | pmid = 12221128 | pmc = 124155 | doi = 10.1091/mbc.E02-02-0112 }}
- Androgen receptor,{{cite journal | vauthors = Cifuentes E, Mataraza JM, Yoshida BA, Menon M, Sacks DB, Barrack ER, Reddy GP | title = Physical and functional interaction of androgen receptor with calmodulin in prostate cancer cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 2 | pages = 464–469 | date = January 2004 | pmid = 14695896 | pmc = 327170 | doi = 10.1073/pnas.0307161101 | doi-access = free | bibcode = 2004PNAS..101..464C }}
- IQGAP1,{{cite journal | vauthors = Li Z, Sacks DB | title = Elucidation of the interaction of calmodulin with the IQ motifs of IQGAP1 | journal = The Journal of Biological Chemistry | volume = 278 | issue = 6 | pages = 4347–4352 | date = February 2003 | pmid = 12446675 | doi = 10.1074/jbc.M208579200 | doi-access = free }}{{cite journal | vauthors = Briggs MW, Li Z, Sacks DB | title = IQGAP1-mediated stimulation of transcriptional co-activation by beta-catenin is modulated by calmodulin | journal = The Journal of Biological Chemistry | volume = 277 | issue = 9 | pages = 7453–7465 | date = March 2002 | pmid = 11734550 | doi = 10.1074/jbc.M104315200 | doi-access = free }}
- PPEF1,{{cite journal | vauthors = Kutuzov MA, Solov'eva OV, Andreeva AV, Bennett N | title = Protein Ser/Thr phosphatases PPEF interact with calmodulin | journal = Biochemical and Biophysical Research Communications | volume = 293 | issue = 3 | pages = 1047–1052 | date = May 2002 | pmid = 12051765 | doi = 10.1016/S0006-291X(02)00338-8 }} and
- TRPV1.{{cite journal | vauthors = Numazaki M, Tominaga T, Takeuchi K, Murayama N, Toyooka H, Tominaga M | title = Structural determinant of TRPV1 desensitization interacts with calmodulin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 13 | pages = 8002–8006 | date = June 2003 | pmid = 12808128 | pmc = 164702 | doi = 10.1073/pnas.1337252100 | doi-access = free | bibcode = 2003PNAS..100.8002N }}
Mutations
Mutations of CALM1 CALM2 or CALM3 can lead to critical cardiac deficiencies including long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT).{{cite journal | vauthors = Hussey JW, Limpitikul WB, Dick IE | title = Calmodulin Mutations in Human Disease | journal = Channels | volume = 17 | issue = 1 | pages = 2165278 | date = December 2023 | pmid = 36629534 | pmc = 9839377 | doi = 10.1080/19336950.2023.2165278 }} 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.
References
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Further reading
{{refbegin | 2}}
- {{cite journal | vauthors = Zhang M, Yuan T | title = Molecular mechanisms of calmodulin's functional versatility | journal = Biochemistry and Cell Biology | volume = 76 | issue = 2–3 | pages = 313–323 | year = 1999 | pmid = 9923700 | doi = 10.1139/bcb-76-2-3-313 }}
- {{cite journal | vauthors = Gusev NB | title = Some properties of caldesmon and calponin and the participation of these proteins in regulation of smooth muscle contraction and cytoskeleton formation | journal = Biochemistry. Biokhimiia | volume = 66 | issue = 10 | pages = 1112–1121 | date = October 2001 | pmid = 11736632 | doi = 10.1023/A:1012480829618 | s2cid = 310781 }}
- {{cite journal | vauthors = Benaim G, Villalobo A | title = Phosphorylation of calmodulin. Functional implications | journal = European Journal of Biochemistry | volume = 269 | issue = 15 | pages = 3619–3631 | date = August 2002 | pmid = 12153558 | doi = 10.1046/j.1432-1033.2002.03038.x | hdl-access = free | hdl = 10261/79981 }}
- {{cite journal | vauthors = Trudeau MC, Zagotta WN | title = Calcium/calmodulin modulation of olfactory and rod cyclic nucleotide-gated ion channels | journal = The Journal of Biological Chemistry | volume = 278 | issue = 21 | pages = 18705–18708 | date = May 2003 | pmid = 12626507 | doi = 10.1074/jbc.R300001200 | doi-access = free }}
{{refend}}
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