Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase 1

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101795

Synonyms

Historical Background

The contraction and relaxation of skeletal muscle is regulated by the concomitant rise and fall of the cytoplasmic calcium level. The Ca2+ is released from the sarcoplasmic reticulum by ryanodine receptor and taken back to the SR by SERCA pumps. The idea of a relaxing factor had been put forward for a long time by many researchers seeking for control mechanism of muscle function. The successful candidate was found in a high-speed pellet of rabbit white skeletal muscle capable of hydrolyzing ATP in Ca2+- and Mg2+-dependent manner and requiring the presence of phospholipids. The dependence on phospholipids and incompatibility to detergents implicated that self-forming sealed vesicles accumulated calcium in an ATP-dependent manner (MacLennan 1970). Since this pellet contained remnants of transversal tubules and self-sealed vesicles, it was apparent that its major constituent was the sarcoplasmic reticulum. Based on this, the pump that accumulated calcium into the vesicles and required magnesium was named sarcoplasmic reticulum (SR) Ca2+- and Mg2+-dependent ATPase. The first isolation of this protein has been done from white muscle of rabbit by sixfold purification (MacLennan 1970) well demonstrating its high abundance in the SR. Facilitated by the relatively easy isolation and homology with the other members of the Ca2+ pump family, information collected about this pump of rabbit white muscle has pioneered research on similar isoforms. In the next almost 20 years, this pump and its isoforms were still called SR-calcium ATPases since the acronym SERCA was introduced only later when the third gene coding for such organelle pump was described by Burk et al. (1989).

The Structure and Activity Cycle of SERCA1

The amino acid sequence and structure of a Ca2+-Mg2+-dependent ATPase from rabbit white muscle was deduced from sequence of cloned complementary DNA (MacLennan et al. 1985). The protein of about 110 kDa had three cytoplasmic domains connected to the ten transmembrane helices with narrow penta-helical stalks. According to this model, one of the cytoplasmic domains would be an actuator (A) releasing the other (N) on binding Ca2+ to the stalks. The nucleotide-binding domain (N) would bind ATP and phosphorylate an aspartate side chain of the third cytoplasmic domain called P inducing conformation change and translocation of Ca2+ from high-affinity binding site on the stalk. Together with the gene of rabbit white muscle Ca2+ ATPase, a paralog Ca2+ ATPase expressed in slow muscle and heart was also cloned (Brandl et al. 1986). This was relevant from the physiology aspect since both slow and heart muscle relaxes at different speed than white fast muscle and it was just the beginning of the discovery of the multiple isoforms of SERCA1-3 pumps. The Ca2+ ATPase from white muscle (later termed SERCA1 by Burk et al. (1989)) is coded by the ATP2A1 and had two almost identical full cDNAs, (confined as SERCA1a and SERCA1b). These are C-terminal variants made by alternative splicing of exon 22. Splicing out of exon 22 with introns in embryonic, neonatal, and developing muscle results in SERCA1b and retaining exon 22 in adult muscle gives rise to SERCA1a (Brandl et al. 1987). The first stop code is in exon 22 (starting immediately on its third nucleotide) but after neonatal splicing the second stop code in exon 23 comes into command. Exon 23 codes with seven amino acids more than exon 22 and because of this the shorter neonatal mRNA translates paradoxically a longer protein while the adult form has a glycine at the C-terminal instead of the DPEDERRK octapeptide. The rest of the two mRNAs is completely identical. The role of the C-terminal SERCA1b tail is still enigmatic although some difference in SERCA1a and SERCA1b calcium transport capacity has been found (Zhao et al. 2015). The C-terminal tail of SERCA1b – probably because of lack of sufficient resources – could not be enlighten by the highest 2.6 Å resolution atomic structure (summarized in Fig. 1a) like it was done for SERCA1a (Toyoshima et al. 2000) but the rest of the molecule was studied in details and gave a refined model compared to the one deduced from cDNA (MacLennan et al. 1985). The deduced structure revealed that SR Ca2+ ATPase is a single polypeptide that has similarity to the group of P-type ATPases and based on special homology in the P-domain together with this group to the superfamily of haloacid-dehalogenases (Toyoshima et al. 2000). The pump besides the three main cytoplasmic had one transmembrane domain containing ten well-separated helices (M1–10). The order of these domains on the sequence from N-terminal to C-terminal is started by a short part of the A (actuator) domain then interrupted by the M1, M2 helices of the transmembrane domain. The rest of the A domain in the beginning (MacLennan et al. 1985) was entitled as a transductor domain but later the crystallography studies suggested its designation also as an actuator. This second part of the A domain has one of the tryptic sites and connected to the M3 and M4 transmembrane parts then it continues with the first sequence of the P domain. The P domain is interrupted by N that is having the second tryptic sites followed by the rest of the P domain. The molecule continues with the M5–M10 domains, among these M6 and M7 are connected by a relative longer sequence and M7 and M8 with a small intraluminal loop. The pump binds two calcium ions and transfers them on account of hydrolyzing one ATP into ADP. In the following decade after isolation of SERCA1 cDNAs, the significance of a number of amino acid in the sequence were analyzed in great detail by in vitro mutagenesis and compared to the crystalized conformation stages (Toyoshima 2009).
Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase 1, Fig. 1

Architecture of Ca2+ ATPase and its ion pumping mechanism. (a) A ribbon representation of Ca2+ ATPase in the E1·2Ca2+ state, viewed parallel to the membrane plane. Colors change gradually from the amino terminus (blue) to the carboxy terminus (red). Purple spheres (numbered and circled) represent bound Ca2+. Three cytoplasmic domains (A, N, and P), the α helices in the A-domain (A1–A3) and those in the transmembrane domain (M1–M10) are indicated. M1′ is an amphipathic part of the M1 helix lying on the bilayer surface. Docked ATP is shown in transparent space fill. Several key residues – E183 (A), F487, and R560 (N, ATP binding), D351 (phosphorylation site), D627, and D703 (P) are shown in balland-stick. Axis of rotation (or tilt) of the A-domain is indicated with thin orange line. PDB accession code is 1SU4 (E1·2Ca2+). (b) A cartoon illustrating the structural changes of the Ca2+ ATPase during the reaction cycle, based on the crystal structures in seven different states (Figure and legend is taken from Fig. 1 of Toyoshima (2009) with permission)

The major steps of the catalytic cycle (Fig. 1b) involve the transitions between the two major conformation sates E1 and E2. The E1 conformation state binds two Ca2+ with high-affinity Ca2+ binding sites facing the cytoplasm. The E2 conformation state releases Ca2+ when the binding sites are facing the SR lumen and have low affinity. The ATP and two Ca2+ binds to E1 from the cytosolic side. The ATP is hydrolyzed to ADP and the Ca2+ is occluded by the transmembrane helices in the 2Ca2+E1P conformation. This high energy state changes conformation to E2P while releases ADP, then the binding sites face the lumenal space, open and release the two Ca2+ because of low affinity. The E2P hydrolyzes out the inorganic phosphate and the cycle closes with transformation of E2 to E1.

The characteristics of SERCA1 seem to be depending on species of the source since the pump from bovine muscle has lower catalytic activity compared to that from rabbit (Sacchetto et al. 2012). The authors found that this might be explained by the difference in region connecting M7 and M8 that is longer and more protruding into the SR lumen in bovine than in rabbit.

SERCA1 Inhibitors and Regulators

About a hundred exogenous inhibitors of wide range of structure have been identified for SERCA (reviewed by Michelangeli and East (2011)). Among them, probably the thapsigargin and cyclopiazonic acid are the most frequently used ones. These substances helped better understanding the structure and function of SERCA1.

Endogen SERCA1 activity can be regulated by pH, the Ca2+ in the cytoplasm (less in SR lumen), the ATP/ADP ratio, covalent modifications (e.g., phosphorylation, nitrosylation), and hormones (e.g., thyroxin), but most of the knowledge is accumulated about two small endogenous peptide, phospholamban (PLB) and sarcolipin (SLN) that are homologous with each other. The molecular interaction of these peptides with SERCA1a is analyzed in detail and revealed that they bound to different conformations (Sahoo et al. 2013; Winther et al. 2013). However, based on its coexpression in fast-glycolytic skeletal muscle, preferably sarcolipin seems to have primary importance for SERCA1a but both SLN and PLB are coexpressed, for example, in human vastus lateralis (Fajardo et al. 2013) and can be potentially significant for SERCA1b in myotubes and developing fibers. Only SLN can bind in the presence of Ca and uncoupling ATPase activity from pumping and stimulate heat production (Sahoo et al. 2013). Recently, open reading frames have been found in long (previously annotated noncoding) RNAs coding for a whole family of endogenous peptides like myoregulin (MLN) that is expressed in most skeletal muscles and also in myotube formation where it may regulate SERCA1 (Anderson et al. 2015) including SERCA1b activity.

SERCA1 Expression and Function

The role of SERCA1a is to establish a 10,000-fold concentration gradient across the membrane of sarcoplasmic reticulum (Toyoshima 2009). This function is best known in relaxation of fast glycolytic muscle but it has also thermogenic function when upregulated by thyroid hormone in skeletal muscle and brown adipose tissue (Arruda et al. 2008). SERCA1a is expressed specifically in fast-glycolytic muscle fibers (Brandl et al. 1986) but SERCA1b is the dominant isoform in development of both fast-glycolytic and slow-oxidative muscles (Zádor and Kósa 2015). Certain conditions like overload induce the neonatal splicing without the translation of the protein (Zádor and Kósa 2015) as the expression of SERCA1b is controlled pretranslationally in adult muscle and happens fully only in neonatal and developing muscle (Zádor and Kósa 2015). The role of SERCA1 (probably SERCA1b) is found in relaxation and probably important in store-operated calcium entry (SOCE), a process refilling the calcium depleted SR in developing myotubes, similar to other cells using other SERCAs (reviewed in Zádor and Kósa (2015)). The only functional difference of SERCA1b compared to SERCA1a is the lower tolerance to high intraluminal calcium concentration (Zhao et al. 2015). However, the only structural difference, the eight amino acid tail compared to single glycine at the C-terminal is facing the cytoplasm in each conformation and therefore do not seem to be explanatory for this.

Impact in Pathology

Mutation of SERCA1a has been found associated with Brody disease, an extremely rare disorder (1:10,000,000) characterized by muscular stiffness and low tolerance for exercise (Odermatt et al. 1996). The aberrant splicing of SERCA1 (together with that of the insulin receptor, ryanodine receptor) is associated with myotonic dystrophy (DM), a rare disorder of nonregenerating adult muscle (Kimura et al. 2005). However, the translation of the neonatal pump from the SERCA1b mRNA occurs at variance in the type 1 and type 2 DM (Zhao et al. 2015), although this disease do not show apparent signs of regeneration. The Duchenne muscular dystrophy (DMD) is the most frequently inherited muscle disorder characterized by permanent cycling of degeneration and regeneration of muscle fibers. Although the primary genetic defect is in the X-linked dystrophin gene, DMD is characterized by aberrant calcium metabolism and its symptoms can be alleviated by overexpressing SERCA1 in mouse model (mdx) of the disease (Mázala et al. 2015). Similar to the situation in mdx mice, the ration of SERCA1 to other SERCAs can also change in other pathological conditions like diabetes and denervation (reviewed in Zádor and Kósa (2015)).

Truncated SERCAs

Novel splice variants were cloned from human liver cDNA libraries in which exon 11 spliced out with or without exon 4 because of the premature stop in exon 12 results in coding truncated isoforms S1T+4 and S1T-4, respectively. Thus, S1T+4 contains 417, while S1T-4 contains 382 amino acid residues – that means they lack a part of the P domain, the entire N domain, and the transmembrane domains M5–M10 in S1T+4 and in addition, the absence of a part M1 and the entire M2 in S1T-4. The contrast between human SERCA1a and the truncated S1T isoforms is also obvious at the level of molecular weight; the full SERCA1a containing 994 amino acid residues is 109 kDa opposing the 46 kDa S1T+4 and 43 kDa and S1T-4. The truncated S1T isoforms lack calcium pump activity but increase Ca2+ leakage from ER. When expressed in immortalized cell culture, S1T proteins colocalize with SERCA1 (and SERCA2b) in ER and behaves consistent with the hypothesis that the homodimers form cation channel. The truncated SERCA1-s are expressed in human adult and fetal liver and kidney (Chami et al. 2001).

Summary

SERCA1a is an important player of calcium metabolism in muscle relaxation of fast-glycolytic muscle fibers and of heat generation in skeletal muscle and brown adipose tissue. Its neonatal isoform, SERCA1b also capable of fulfilling similar functions and in addition, it has a not fully discovered role in muscle development and contribution to SOCE. The crystal structures determined cover almost the entire reaction cycle of SERCA1 but there are still “white spots” in its conformation change. The unknown conformation stages might be enlightened by the action of the range of novel peptide inhibitors. The role of SERCA1b tail is also waiting to be described, either by novel conformations or interactions with other proteins. Last but not least, the structure of SERCA1 from not yet analyzed sources (other than the rabbit white muscle) might contribute with valuable details to a more complete understanding.

Notes

Acknowledgment

Thank you to C. Toyoshima for allowing to use images and legends of Fig. 1 from his review article (Toyoshima 2009).

References

  1. Anderson DM, Anderson KM, Chang CL, Makarewich CA, Nelson BR, McAnally JR, et al. A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell. 2015;160:595–606.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Arruda AP, Ketzer LA, Nigro M, Galina A, Carvalho DP, de Meis L. Cold tolerance in hypothyroid rabbits: role of skeletal muscle mitochondria and sarcoplasmic reticulum Ca2+ ATPase isoform 1 heat production. Endocrinology. 2008;149:6262–71.PubMedCrossRefGoogle Scholar
  3. Brandl CJ, Green NM, Korczak B, MacLennan DH. Two Ca2+ ATPase genes: homologies and mechanistic implications of deduced amino acid sequences. Cell. 1986;44:597–607.PubMedCrossRefGoogle Scholar
  4. Brandl CJ, deLeon S, Martin DR, MacLennan DH. Adult forms of the Ca2+ATPase of sarcoplasmic reticulum. Expression in developing skeletal muscle. J Biol Chem. 1987;262:3768–74.PubMedGoogle Scholar
  5. Burk SE, Lytton J, MacLennan DH, Shull GE. cDNA cloning, functional expression, and mRNA tissue distribution of a third organellar Ca2+ pump. J Biol Chem. 1989;264:18561–8.PubMedGoogle Scholar
  6. Chami M, Gozuacik D, Lagorce D, Brini M, Falson P, Peaucellier G, et al. SERCA1 truncated proteins unable to pump calcium reduce the endoplasmic reticulum calcium concentration and induce apoptosis. J Cell Biol. 2001;153:1301–14.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Fajardo VA, Bombardier E, Vigna C, Devji T, Bloemberg D, Gamu D, et al. Co-expression of SERCA isoforms, phospholamban and sarcolipin in human skeletal muscle fibers. PLoS One. 2013;8:e84304.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Kimura T, Nakamori M, Lueck JD, Pouliquin P, Aoike F, Fujimura H, et al. Altered mRNA splicing of the skeletal muscle ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase in myotonic dystrophy type 1. Hum Mol Genet. 2005;14:2189–200.PubMedCrossRefGoogle Scholar
  9. MacLennan DH. Purification and properties of an adenosine triphosphatase from sarcoplasmic reticulum. J Biol Chem. 1970;245:4508–18.PubMedGoogle Scholar
  10. MacLennan DH, Brandl CJ, Korczak B, Green NM. Amino-acid sequence of a Ca2+ + Mg2+-dependent ATPase from rabbit muscle sarcoplasmic reticulum, deduced from its complementary DNA sequence. Nature. 1985;316:696–700.PubMedCrossRefGoogle Scholar
  11. Mázala DA, Pratt SJ, Chen D, Molkentin JD, Lovering RM, Chin ER. SERCA1 overexpression minimizes skeletal muscle damage in dystrophic mouse models. Am J Phys Cell Phys. 2015;308:C699–709.CrossRefGoogle Scholar
  12. Michelangeli F, East JM. A diversity of SERCA Ca2+ pump inhibitors. Biochem Soc Trans. 2011;39:789–97.PubMedCrossRefGoogle Scholar
  13. Odermatt A, Taschner PE, Khanna VK, Busch HF, Karpati G, Jablecki CK, et al. Mutations in the gene-encoding SERCA1, the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase, are associated with Brody disease. Nat Genet. 1996;14:191–4.PubMedCrossRefGoogle Scholar
  14. Sacchetto R, Bertipaglia I, Giannetti S, Cendron L, Mascarello F, Damiani E, et al. Crystal structure of sarcoplasmic reticulum Ca2+-ATPase (SERCA) from bovine muscle. J Struct Biol. 2012;178:38–44.PubMedCrossRefGoogle Scholar
  15. Sahoo SK, Shaikh SA, Sopariwala DH, Bal NC, Periasamy M. Sarcolipin protein interaction with sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) is distinct from phospholamban protein, and only sarcolipin can promote uncoupling of the SERCA pump. J Biol Chem. 2013;288:6881–9.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Toyoshima C. How Ca2+-ATPase pumps ions across the sarcoplasmic reticulum membrane. Biochim Biophys Acta. 2009;1793:941–6.PubMedCrossRefGoogle Scholar
  17. Toyoshima C, Nakasako M, Nomura H, Ogawa H. Crystal structure of the calcium pump of sarcoplasmic reticulum at 2.6 A resolution. Nature. 2000;405:647–55.PubMedCrossRefGoogle Scholar
  18. Winther AM, Bublitz M, Karlsen JL, Møller JV, Hansen JB, Nissen P, Buch-Pedersen MJ. The sarcolipin-bound calcium pump stabilizes calcium sites exposed to the cytoplasm. Nature. 2013;495:265–9.PubMedCrossRefGoogle Scholar
  19. Zádor E, Kósa M. The neonatal sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA1b): a neglected pump in scope. Pflugers Arch. 2015;467:1395–401.PubMedCrossRefGoogle Scholar
  20. Zhao Y, Ogawa H, Yonekura S, Mitsuhashi H, Mitsuhashi S, Nishino I, et al. Functional analysis of SERCA1b, a highly expressed SERCA1 variant in myotonic dystrophy type 1 muscle. Biochim Biophys Acta. 2015;1852:2042–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Institute of Biochemistry, Faculty of MedicineUniversity of SzegedSzegedHungary