ATP2A1 explained

Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 (SERCA1) also known as Calcium pump 1, is an enzyme that in humans is encoded by the ATP2A1 gene.^{[1] [2]}

Function

This gene encodes one of the SERCA Ca²⁺-ATPases, which are intracellular pumps located in the sarcoplasmic or endoplasmic reticula of muscle cells. This enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen, and is involved in muscular excitation and contraction.^[1]

Clinical significance

Mutations in this gene cause some autosomal recessive forms of Brody disease, characterized by increasing impairment of muscular relaxation during exercise. Alternative splicing results in two transcript variants encoding different isoforms.^[1] Alternative splicing of ATP2A1 is also implicated in myotonic dystrophy type 1.

ATP2A1 SERCA pumps were very strongly down regulated in amyotrophic lateral sclerosis.^[3]

Interactions

ATP2A1 has been shown to interact with:

• SLN,^[4] and
• PLN.^{[5] [6] [7]}

Further reading

• Baba-Aissa F, Raeymaekers L, Wuytack F . Distribution and isoform diversity of the organellar Ca²⁺ pumps in the brain. . Mol. Chem. Neuropathol. . 33 . 3 . 199–208 . 1998 . 9642673 . 10.1007/BF02815182 . etal.
• Callen DF, Baker E, Lane S . Regional mapping of the Batten disease locus (CLN3) to human chromosome 16p12. . Am. J. Hum. Genet. . 49 . 6 . 1372–7 . 1992 . 1746562 . 1702406 . etal.
• MacLennan DH, Brandl CJ, Champaneria S . Fast-twitch and slow-twitch/cardiac Ca²⁺ ATPase genes map to human chromosomes 16 and 12. . Somat. Cell Mol. Genet. . 13 . 4 . 341–6 . 1988 . 2842876 . 10.1007/BF01534928 . 1475105 . etal.
• Brandl CJ, Green NM, Korczak B, MacLennan DH . Two Ca²⁺ ATPase genes: homologies and mechanistic implications of deduced amino acid sequences. . Cell . 44 . 4 . 597–607 . 1986 . 2936465 . 10.1016/0092-8674(86)90269-2 . 43419264 .
• Benders AA, Wevers RA, Veerkamp JH . Ion transport in human skeletal muscle cells: disturbances in myotonic dystrophy and Brody's disease. . Acta Physiol. Scand. . 156 . 3 . 355–67 . 1996 . 8729696 . 10.1046/j.1365-201X.1996.202000.x . 2066/24180 . free .
• Zhang Y, Fujii J, Phillips MS . Characterization of cDNA and genomic DNA encoding SERCA1, the Ca²⁺-ATPase of human fast-twitch skeletal muscle sarcoplasmic reticulum, and its elimination as a candidate gene for Brody disease. . Genomics . 30 . 3 . 415–24 . 1997 . 8825625 . 10.1006/geno.1995.1259 . etal. free .
• Odermatt A, Taschner PE, Khanna VK . Mutations in the gene-encoding SERCA1, the fast-twitch skeletal muscle sarcoplasmic reticulum Ca²⁺ ATPase, are associated with Brody disease. . Nat. Genet. . 14 . 2 . 191–4 . 1996 . 8841193 . 10.1038/ng1096-191 . 22726202 . etal.
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery. . Genome Res. . 6 . 9 . 791–806 . 1997 . 8889548 . 10.1101/gr.6.9.791 . free .
• Algenstaedt P, Antonetti DA, Yaffe MB, Kahn CR . Insulin receptor substrate proteins create a link between the tyrosine phosphorylation cascade and the Ca²⁺-ATPases in muscle and heart. . J. Biol. Chem. . 272 . 38 . 23696–702 . 1997 . 9295312 . 10.1074/jbc.272.38.23696 . free .
• Odermatt A, Taschner PE, Scherer SW . Characterization of the gene encoding human sarcolipin (SLN), a proteolipid associated with SERCA1: absence of structural mutations in five patients with Brody disease. . Genomics . 45 . 3 . 541–53 . 1998 . 9367679 . 10.1006/geno.1997.4967 . etal. 2066/25426 . 41989102 . free .
• MacLennan DH, Rice WJ, Odermatt A . Structure/function analysis of the Ca²⁺ binding and translocation domain of SERCA1 and the role in Brody disease of the ATP2A1 gene encoding SERCA1. . Ann. N. Y. Acad. Sci. . 834 . 1 Na/K–ATPase a. 175–85 . 1998 . 9405806 . 10.1111/j.1749-6632.1997.tb52249.x . 38068023 .
• Odermatt A, Becker S, Khanna VK . Sarcolipin regulates the activity of SERCA1, the fast-twitch skeletal muscle sarcoplasmic reticulum Ca²⁺-ATPase. . J. Biol. Chem. . 273 . 20 . 12360–9 . 1998 . 9575189 . 10.1074/jbc.273.20.12360 . etal. free .
• Asahi M, Kimura Y, Kurzydlowski K . Transmembrane helix M6 in sarco(endo)plasmic reticulum Ca²⁺-ATPase forms a functional interaction site with phospholamban. Evidence for physical interactions at other sites. . J. Biol. Chem. . 274 . 46 . 32855–62 . 2000 . 10551848 . 10.1074/jbc.274.46.32855 . etal. free .
• Odermatt A, Barton K, Khanna VK . The mutation of Pro789 to Leu reduces the activity of the fast-twitch skeletal muscle sarco(endo)plasmic reticulum Ca²⁺ ATPase (SERCA1) and is associated with Brody disease. . Hum. Genet. . 106 . 5 . 482–91 . 2000 . 10914677 . 10.1007/s004390000297 . 31756080 . etal.
• Daiho T, Yamasaki K, Saino T . Mutations of either or both Cys876 and Cys888 residues of sarcoplasmic reticulum Ca²⁺ATPase result in a complete loss of Ca²⁺ transport activity without a loss of Ca²⁺-dependent ATPase activity. Role of the CYS876-CYS888 disulfide bond. . J. Biol. Chem. . 276 . 35 . 32771–8 . 2001 . 11438520 . 10.1074/jbc.M101229200 . etal. free .
• Asahi M, Green NM, Kurzydlowski K . Phospholamban domain IB forms an interaction site with the loop between transmembrane helices M6 and M7 of sarco(endo)plasmic reticulum Ca²⁺ ATPases. . Proc. Natl. Acad. Sci. U.S.A. . 98 . 18 . 10061–6 . 2001 . 11526231 . 10.1073/pnas.181348298 . 56915 . 2001PNAS...9810061A . etal. free .
• Strausberg RL, Feingold EA, Grouse LH . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . etal. free .
• Pieske B, Maier LS, Schmidt-Schweda S . Sarcoplasmic reticulum Ca²⁺ load in human heart failure. . Basic Res. Cardiol. . 97 Suppl 1 . 7. I63–71 . 2002 . 12479237 . 10.1007/s003950200032. 22854208 .
• Toyoshima C, Asahi M, Sugita Y . Modeling of the inhibitory interaction of phospholamban with the Ca²⁺ ATPase. . Proc. Natl. Acad. Sci. U.S.A. . 100 . 2 . 467–72 . 2003 . 12525698 . 10.1073/pnas.0237326100 . 141018 . 2003PNAS..100..467T . etal. free .

Notes and References

1. Web site: Entrez Gene: ATP2A1 ATPase, Ca⁺⁺ transporting, cardiac muscle, fast twitch 1.
2. Web site: UniProt . www.uniprot.org . 1 August 2023.
3. 10.3389/fphys.2017.00980. free. Co-expression Network Approach Reveals Functional Similarities among Diseases Affecting Human Skeletal Muscle. 2017. Mukund. Kavitha. Subramaniam. Shankar. Frontiers in Physiology. 8. 980. 29249983. 5717538.
4. April 2003 . Asahi M, Sugita Y, Kurzydlowski K, De Leon S, Tada M, Toyoshima C, MacLennan DH . Sarcolipin regulates sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) by binding to transmembrane helices alone or in association with phospholamban . Proc. Natl. Acad. Sci. U.S.A. . 100 . 9 . 5040–5 . 12692302 . 154294 . 10.1073/pnas.0330962100. 2003PNAS..100.5040A . free .
5. July 2002 . Asahi M, Kurzydlowski K, Tada M, MacLennan DH . Sarcolipin inhibits polymerization of phospholamban to induce superinhibition of sarco(endo)plasmic reticulum Ca2+-ATPases (SERCAs) . J. Biol. Chem. . 277 . 30 . 26725–8 . 12032137 . 10.1074/jbc.C200269200. free .
6. November 1999 . Asahi M, Kimura Y, Kurzydlowski K, Tada M, MacLennan DH . Transmembrane helix M6 in sarco(endo)plasmic reticulum Ca(2+)-ATPase forms a functional interaction site with phospholamban. Evidence for physical interactions at other sites . J. Biol. Chem. . 274 . 46 . 32855–62 . 10551848 . 10.1074/jbc.274.46.32855. free .
7. August 2001 . Asahi M, Green NM, Kurzydlowski K, Tada M, MacLennan DH . Phospholamban domain IB forms an interaction site with the loop between transmembrane helices M6 and M7 of sarco(endo)plasmic reticulum Ca2+ ATPases . Proc. Natl. Acad. Sci. U.S.A. . 98 . 18 . 10061–6 . 11526231 . 56915 . 10.1073/pnas.181348298. 2001PNAS...9810061A . free .