Structure-Function Relationship of the SERCA Pump and Its Regulation by Phospholamban and Sarcolipin

  • Przemek A. Gorski
  • Delaine K. Ceholski
  • Howard S. Young
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 981)

Abstract

Calcium is a universal second messenger involved in diverse cellular processes, including excitation-contraction coupling in muscle. The contraction and relaxation of cardiac muscle cells are regulated by the cyclic movement of calcium primarily between the extracellular space, the cytoplasm and the sarcoplasmic reticulum (SR). The rapid removal of calcium from the cytosol is primarily facilitated by the sarco(endo)plasmic reticulum calcium ATPase (SERCA) which pumps calcium back into the SR lumen and thereby controls the amount of calcium in the SR. The most studied member of the P-type ATPase family, SERCA has multiple tissue- and cell-specific isoforms and is primarily regulated by two peptides in muscle, phospholamban and sarcolipin. The multifaceted regulation of SERCA via these peptides is exemplified in the biological fine-tuning of their independent oligomerization and regulation. In this chapter, we overview the structure-function relationship of SERCA and its peptide modulators, detailing the regulation of the complexes and summarizing their physiological and disease relevance.

Keywords

Calcium Sarcoplasmic reticulum Calcium ATPase Phospholamban Sarcolipin 

References

  1. 1.
    Carafoli E (2002) Calcium signaling: a tale for all seasons. Proc Natl Acad Sci USA 99:1115–1122CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Bers DM (2002) Cardiac excitation-contraction coupling. Nature 415:198–205CrossRefPubMedGoogle Scholar
  3. 3.
    Periasamy M, Kalyanasundaram A (2007) SERCA pump isoforms: their role in calcium transport and disease. Muscle Nerve 35:430–442CrossRefPubMedGoogle Scholar
  4. 4.
    Bhupathy P, Babu GJ, Periasamy M (2007) Sarcolipin and phospholamban as regulators of cardiac sarcoplasmic reticulum Ca2+ ATPase. J Mol Cell Cardiol 42:903–911CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ji Y et al (1999) SERCA1a can functionally substitute for SERCA2a in the heart. Am J Phys 276:H89–H97Google Scholar
  6. 6.
    Loukianov E et al (1998) Enhanced myocardial contractility and increased Ca2+ transport function in transgenic hearts expressing the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+-ATPase. Circ Res 83:889–897CrossRefPubMedGoogle Scholar
  7. 7.
    Lalli MJ et al (2001) Sarcoplasmic reticulum Ca(2+) atpase (SERCA) 1a structurally substitutes for SERCA2a in the cardiac sarcoplasmic reticulum and increases cardiac Ca(2+) handling capacity. Circ Res 89:160–167CrossRefPubMedGoogle Scholar
  8. 8.
    MacLennan DH (2000) Ca2+ signalling and muscle disease. Eur J Biochem 267:5291–5297CrossRefPubMedGoogle Scholar
  9. 9.
    Odermatt A et al (1996) Mutations in the gene-encoding SERCA1, the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase, are associated with Brody disease. Nat Genet 14:191–194CrossRefPubMedGoogle Scholar
  10. 10.
    Vangheluwe P et al (2003) Ca2+ transport ATPase isoforms SERCA2a and SERCA2b are targeted to the same sites in the murine heart. Cell Calcium 34:457–464CrossRefPubMedGoogle Scholar
  11. 11.
    MacLennan DH, Kranias EG (2003) Phospholamban: a crucial regulator of cardiac contractility. Nat Rev Mol Cell Biol 4:566–577CrossRefPubMedGoogle Scholar
  12. 12.
    Gunteski-Hamblin AM, Greeb J, Shull GE (1988) A novel Ca2+ pump expressed in brain, kidney, and stomach is encoded by an alternative transcript of the slow-twitch muscle sarcoplasmic reticulum Ca-ATPase gene. Identification of cDNAs encoding Ca2+ and other cation-transporting ATPases using an oligonucleotide probe derived from the ATP-binding site. J Biol Chem 263:15032–15040PubMedGoogle Scholar
  13. 13.
    Verboomen H et al (1992) Functional difference between SERCA2a and SERCA2b Ca2+ pumps and their modulation by phospholamban. Biochem J 286(Pt 2):591–595CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Dally S et al (2006) Ca2+-ATPases in non-failing and failing heart: evidence for a novel cardiac sarco/endoplasmic reticulum Ca2+-ATPase 2 isoform (SERCA2c). Biochem J 395:249–258CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kimura T et al (2005) Altered mRNA splicing of the skeletal muscle ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase in myotonic dystrophy type 1. Hum Mol Genet 14:2189–2200CrossRefPubMedGoogle Scholar
  16. 16.
    Clausen JD et al (2012) Distinct roles of the C-terminal 11th transmembrane helix and luminal extension in the partial reactions determining the high Ca2+ affinity of sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2b (SERCA2b). J Biol Chem 287(39):460–469Google Scholar
  17. 17.
    Wuytack F, Raeymaekers L, Missiaen L (2002) Molecular physiology of the SERCA and SPCA pumps. Cell Calcium 32:279–305CrossRefPubMedGoogle Scholar
  18. 18.
    Periasamy M et al (1999) Impaired cardiac performance in heterozygous mice with a null mutation in the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 (SERCA2) gene. J Biol Chem 274:2556–2562CrossRefPubMedGoogle Scholar
  19. 19.
    Wuytack F et al (1995) The SERCA3-type of organellar Ca2+ pumps. Biosci Rep 15:299–306CrossRefPubMedGoogle Scholar
  20. 20.
    Varadi A et al (1999) Sequence variants of the sarco(endo)plasmic reticulum Ca(2+)-transport ATPase 3 gene (SERCA3) in Caucasian type II diabetic patients (UK Prospective Diabetes Study 48). Diabetologia 42:1240–1243CrossRefPubMedGoogle Scholar
  21. 21.
    Liu LH et al (1997) Defective endothelium-dependent relaxation of vascular smooth muscle and endothelial cell Ca2+ signaling in mice lacking sarco(endo)plasmic reticulum Ca2+-ATPase isoform 3. J Biol Chem 272(30):538–545Google Scholar
  22. 22.
    Xu XY et al (2012) Aberrant SERCA3 expression is closely linked to pathogenesis, invasion, metastasis, and prognosis of gastric carcinomas. Tumour Biol 33:1845–1854CrossRefPubMedGoogle Scholar
  23. 23.
    Arbabian A et al (2013) Modulation of endoplasmic reticulum calcium pump expression during lung cancer cell differentiation. FEBS J 280:5408–5418CrossRefPubMedGoogle Scholar
  24. 24.
    Gelebart P et al (2002) Expression of endomembrane calcium pumps in colon and gastric cancer cells. Induction of SERCA3 expression during differentiation. J Biol Chem 277:26310–26320CrossRefPubMedGoogle Scholar
  25. 25.
    Papp B, Brouland JP (2011) Altered endoplasmic reticulum calcium pump expression during breast tumorigenesis. Breast Cancer (Auckl) 5:163–174Google Scholar
  26. 26.
    Kuhlbrandt W (2004) Biology, structure and mechanism of P-type ATPases. Nat Rev Mol Cell Biol 5:282–295CrossRefPubMedGoogle Scholar
  27. 27.
    Albers RW (1967) Biochemical aspects of active transport. Annu Rev Biochem 36:727–756CrossRefPubMedGoogle Scholar
  28. 28.
    Moller JV et al (2010) The sarcoplasmic Ca2+-ATPase: design of a perfect chemi-osmotic pump. Q Rev Biophys 43:501–566CrossRefPubMedGoogle Scholar
  29. 29.
    Olesen C et al (2007) The structural basis of calcium transport by the calcium pump. Nature 450:1036–1042CrossRefPubMedGoogle Scholar
  30. 30.
    Moller JV et al (2005) Transport mechanism of the sarcoplasmic reticulum Ca2+ -ATPase pump. Curr Opin Struct Biol 15:387–393CrossRefPubMedGoogle Scholar
  31. 31.
    Jensen AM et al (2006) Modulatory and catalytic modes of ATP binding by the calcium pump. EMBO J 25:2305–2314CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Moncoq K, Trieber CA, Young HS (2007) The molecular basis for cyclopiazonic acid inhibition of the sarcoplasmic reticulum calcium pump. J Biol Chem 282:9748–9757CrossRefPubMedGoogle Scholar
  33. 33.
    Laursen M et al (2009) Cyclopiazonic acid is complexed to a divalent metal ion when bound to the sarcoplasmic reticulum Ca2+-ATPase. J Biol Chem 284(13):513–518Google Scholar
  34. 34.
    MacLennan DH et al (1985) Amino-acid sequence of a Ca2+ + Mg2+-dependent ATPase from rabbit muscle sarcoplasmic reticulum, deduced from its complementary DNA sequence. Nature 316:696–700CrossRefPubMedGoogle Scholar
  35. 35.
    Lee AG, East JM (2001) What the structure of a calcium pump tells us about its mechanism. Biochem J 356:665–683CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Dux L, Martonosi A (1983) Two-dimensional arrays of proteins in sarcoplasmic reticulum and purified Ca2+-ATPase vesicles treated with vanadate. J Biol Chem 258:2599–2603PubMedGoogle Scholar
  37. 37.
    Toyoshima C, Sasabe H, Stokes DL (1993) Three-dimensional cryo-electron microscopy of the calcium ion pump in the sarcoplasmic reticulum membrane. Nature 362:467–471CrossRefPubMedGoogle Scholar
  38. 38.
    Zhang P et al (1998) Structure of the calcium pump from sarcoplasmic reticulum at 8-A resolution. Nature 392:835–839CrossRefPubMedGoogle Scholar
  39. 39.
    Toyoshima C et al (2000) Crystal structure of the calcium pump of sarcoplasmic reticulum at 2.6 A resolution. Nature 405:647–655CrossRefPubMedGoogle Scholar
  40. 40.
    Zhang Z et al (2000) Detailed characterization of the cooperative mechanism of Ca(2+) binding and catalytic activation in the Ca(2+) transport (SERCA) ATPase. Biochemistry 39:8758–8767CrossRefPubMedGoogle Scholar
  41. 41.
    Toyoshima C, Nomura H (2002) Structural changes in the calcium pump accompanying the dissociation of calcium. Nature 418:605–611CrossRefPubMedGoogle Scholar
  42. 42.
    Clausen JD et al (2008) Critical interaction of actuator domain residues arginine 174, isoleucine 188, and lysine 205 with modulatory nucleotide in sarcoplasmic reticulum Ca2+-ATPase. J Biol Chem 283(35):703–714Google Scholar
  43. 43.
    Sorensen TL, Moller JV, Nissen P (2004) Phosphoryl transfer and calcium ion occlusion in the calcium pump. Science 304:1672–1675CrossRefPubMedGoogle Scholar
  44. 44.
    Toyoshima C et al (2003) Modeling of the inhibitory interaction of phospholamban with the Ca2+ ATPase. Proc Natl Acad Sci USA 100:467–472CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Drachmann ND et al (2014) Comparing crystal structures of Ca(2+) -ATPase in the presence of different lipids. FEBS J 281:4249–4262CrossRefPubMedGoogle Scholar
  46. 46.
    Akin BL et al (2013) The structural basis for phospholamban inhibition of the calcium pump in sarcoplasmic reticulum. J Biol Chem 288(30):181–191Google Scholar
  47. 47.
    Kimura Y et al (1997) Phospholamban inhibitory function is activated by depolymerization. J Biol Chem 272(15):61–64Google Scholar
  48. 48.
    Robia SL et al (2007) Forster transfer recovery reveals that phospholamban exchanges slowly from pentamers but rapidly from the SERCA regulatory complex. Circ Res 101:1123–1129CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Cornea RL et al (2000) Reexamination of the role of the leucine/isoleucine zipper residues of phospholamban in inhibition of the Ca2+ pump of cardiac sarcoplasmic reticulum. J Biol Chem 275(41):487–494Google Scholar
  50. 50.
    Kimura Y et al (1998) Phospholamban domain Ib mutations influence functional interactions with the Ca2+-ATPase isoform of cardiac sarcoplasmic reticulum. J Biol Chem 273(14):238–241Google Scholar
  51. 51.
    Karim CB et al (2001) Role of cysteine residues in structural stability and function of a transmembrane helix bundle. J Biol Chem 276(38):814–819Google Scholar
  52. 52.
    Karim CB et al (1998) Cysteine reactivity and oligomeric structures of phospholamban and its mutants. Biochemistry 37:12074–12081CrossRefPubMedGoogle Scholar
  53. 53.
    Becucci L et al (2009) On the function of pentameric phospholamban: ion channel or storage form? Biophys J 96:L60–L62CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Kovacs RJ et al (1988) Phospholamban forms Ca2+-selective channels in lipid bilayers. J Biol Chem 263(18):364–368Google Scholar
  55. 55.
    Oxenoid K, Chou JJ (2005) The structure of phospholamban pentamer reveals a channel-like architecture in membranes. Proc Natl Acad Sci USA 102(10):870–875Google Scholar
  56. 56.
    Stokes DL et al (2006) Interactions between Ca2+-ATPase and the pentameric form of phospholamban in two-dimensional co-crystals. Biophys J 90:4213–4223CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Glaves JP et al (2011) Phosphorylation and mutation of phospholamban alter physical interactions with the sarcoplasmic reticulum calcium pump. J Mol Biol 405:707–723CrossRefPubMedGoogle Scholar
  58. 58.
    Chu G et al (1998) Pentameric assembly of phospholamban facilitates inhibition of cardiac function in vivo. J Biol Chem 273(33):674–680Google Scholar
  59. 59.
    Chen Z, Akin BL, Jones LR (2007) Mechanism of reversal of phospholamban inhibition of the cardiac Ca2+-ATPase by protein kinase A and by anti-phospholamban monoclonal antibody 2D12. J Biol Chem 282(20):968–976Google Scholar
  60. 60.
    Cornea RL et al (1997) Mutation and phosphorylation change the oligomeric structure of phospholamban in lipid bilayers. Biochemistry 36:2960–2967CrossRefPubMedGoogle Scholar
  61. 61.
    Oxenoid K, Rice AJ, Chou JJ (2007) Comparing the structure and dynamics of phospholamban pentamer in its unphosphorylated and pseudo-phosphorylated states. Protein Sci 16:1977–1983CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Hou Z, Kelly EM, Robia SL (2008) Phosphomimetic mutations increase phospholamban oligomerization and alter the structure of its regulatory complex. J Biol Chem 283(28):996–9003Google Scholar
  63. 63.
    Wegener AD et al (1986) Proteolytic cleavage of phospholamban purified from canine cardiac sarcoplasmic reticulum vesicles. Generation of a low resolution model of phospholamban structure. J Biol Chem 261:5154–5159PubMedGoogle Scholar
  64. 64.
    Choma C et al (2000) Asparagine-mediated self-association of a model transmembrane helix. Nat Struct Biol 7:161–166CrossRefPubMedGoogle Scholar
  65. 65.
    Afara MR et al (2006) Rational design of peptide inhibitors of the sarcoplasmic reticulum calcium pump. Biochemistry 45:8617–8627CrossRefPubMedGoogle Scholar
  66. 66.
    Afara MR et al (2008) Peptide inhibitors use two related mechanisms to alter the apparent calcium affinity of the sarcoplasmic reticulum calcium pump. Biochemistry 47:9522–9530CrossRefPubMedGoogle Scholar
  67. 67.
    Kimura Y et al (1996) Phospholamban regulates the Ca2+-ATPase through intramembrane interactions. J Biol Chem 271(21):726–731Google Scholar
  68. 68.
    Trieber CA, Afara M, Young HS (2009) Effects of phospholamban transmembrane mutants on the calcium affinity, maximal activity, and cooperativity of the sarcoplasmic reticulum calcium pump. Biochemistry 48:9287–9296CrossRefPubMedGoogle Scholar
  69. 69.
    Toyofuku T et al (1994) Amino acids Glu2 to Ile18 in the cytoplasmic domain of phospholamban are essential for functional association with the Ca(2+)-ATPase of sarcoplasmic reticulum. J Biol Chem 269:3088–3094PubMedGoogle Scholar
  70. 70.
    Kim HW et al (1990) Functional reconstitution of the cardiac sarcoplasmic reticulum Ca2(+)-ATPase with phospholamban in phospholipid vesicles. J Biol Chem 265:1702–1709PubMedGoogle Scholar
  71. 71.
    Sasaki T et al (1992) Molecular mechanism of regulation of Ca2+ pump ATPase by phospholamban in cardiac sarcoplasmic reticulum. Effects of synthetic phospholamban peptides on Ca2+ pump ATPase. J Biol Chem 267:1674–1679PubMedGoogle Scholar
  72. 72.
    Jones LR, Field LJ (1993) Residues 2-25 of phospholamban are insufficient to inhibit Ca2+ transport ATPase of cardiac sarcoplasmic reticulum. J Biol Chem 268(11):486–488Google Scholar
  73. 73.
    Schmitt JP et al (2003) Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. Science 299:1410–1413CrossRefPubMedGoogle Scholar
  74. 74.
    Haghighi K et al (2006) A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy. Proc Natl Acad Sci USA 103:1388–1393CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Medeiros A et al (2011) Mutations in the human phospholamban gene in patients with heart failure. Am Heart J 162(1088–1095):e1Google Scholar
  76. 76.
    Traaseth NJ et al (2009) Structure and topology of monomeric phospholamban in lipid membranes determined by a hybrid solution and solid-state NMR approach. Proc Natl Acad Sci USA 106(10):165–170Google Scholar
  77. 77.
    Lamberth S et al (2000) NMR solution structure of phospholamban. Helvetica Chimica Acta 83:2141–2152CrossRefGoogle Scholar
  78. 78.
    Gustavsson M, Traaseth NJ, Veglia G (2011) Activating and deactivating roles of lipid bilayers on the Ca(2+)-ATPase/phospholamban complex. Biochemistry 50:10367–10374CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Traaseth NJ et al (2007) Spectroscopic validation of the pentameric structure of phospholamban. Proc Natl Acad Sci USA 104(14):676–681Google Scholar
  80. 80.
    Hughes E, Clayton JC, Middleton DA (2009) Cytoplasmic residues of phospholamban interact with membrane surfaces in the presence of SERCA: a new role for phospholipids in the regulation of cardiac calcium cycling? Biochim Biophys Acta 1788:559–566CrossRefPubMedGoogle Scholar
  81. 81.
    James P et al (1989) Nature and site of phospholamban regulation of the Ca2+ pump of sarcoplasmic reticulum. Nature 342:90–92CrossRefPubMedGoogle Scholar
  82. 82.
    Seidel K et al (2008) Structural characterization of Ca2+-ATPase-bound phospholamban in lipid bilayers by solid-state nuclear magnetic resonance (NMR) spectroscopy. Biochemistry 47:4369–4376CrossRefPubMedGoogle Scholar
  83. 83.
    Gustavsson M et al (2013) Allosteric regulation of SERCA by phosphorylation-mediated conformational shift of phospholamban. Proc Natl Acad Sci USA 110(17):338–343Google Scholar
  84. 84.
    Chen Z et al (2003) Spatial and dynamic interactions between phospholamban and the canine cardiac Ca2+ pump revealed with use of heterobifunctional cross-linking agents. J Biol Chem 278(48):348–356CrossRefGoogle Scholar
  85. 85.
    Chen Z, Stokes DL, Jones LR (2005) Role of leucine 31 of phospholamban in structural and functional interactions with the Ca2+ pump of cardiac sarcoplasmic reticulum. J Biol Chem 280(10):530–539Google Scholar
  86. 86.
    Chen Z et al (2006) Cross-linking of C-terminal residues of phospholamban to the Ca2+ pump of cardiac sarcoplasmic reticulum to probe spatial and functional interactions within the transmembrane domain. J Biol Chem 281(14):163–172CrossRefGoogle Scholar
  87. 87.
    Jones LR, Cornea RL, Chen Z (2002) Close proximity between residue 30 of phospholamban and cysteine 318 of the cardiac Ca2+ pump revealed by intermolecular thiol cross-linking. J Biol Chem 277(28):319–329Google Scholar
  88. 88.
    Starling AP et al (1996) The effect of N-terminal acetylation on Ca(2+)-ATPase inhibition by phospholamban. Biochem Biophys Res Commun 226:352–355CrossRefPubMedGoogle Scholar
  89. 89.
    Filice E et al (2011) Crucial role of phospholamban phosphorylation and S-nitrosylation in the negative lusitropism induced by 17beta-estradiol in the male rat heart. Cell Physiol Biochem 28:41–52CrossRefPubMedGoogle Scholar
  90. 90.
    Kranias EG, Hajjar RJ (2017) The phospholamban journey 4 decades after setting out for Ithaka. Circ Res 120:781–783CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Tada M et al (1974) The stimulation of calcium transport in cardiac sarcoplasmic reticulum by adenosine 3′:5′’-monophosphate-dependent protein kinase. J Biol Chem 249:6174–6180PubMedGoogle Scholar
  92. 92.
    Katz AM (1998) Discovery of phospholamban. A personal history. Ann N Y Acad Sci 853:9–19CrossRefPubMedGoogle Scholar
  93. 93.
    Tada M, Kirchberger MA, Katz AM (1975) Phosphorylation of a 22,000-dalton component of the cardiac sarcoplasmic reticulum by adenosine 3′:5′-monophosphate-dependent protein kinase. J Biol Chem 250:2640–2647PubMedGoogle Scholar
  94. 94.
    Catalucci D et al (2009) Akt increases sarcoplasmic reticulum Ca2+ cycling by direct phosphorylation of phospholamban at Thr17. J Biol Chem 284(28):180–187Google Scholar
  95. 95.
    Edes I, Kranias EG (1990) Phospholamban and troponin I are substrates for protein kinase C in vitro but not in intact beating guinea pig hearts. Circ Res 67:394–400CrossRefPubMedGoogle Scholar
  96. 96.
    Chu G, Kranias EG (2002) Functional interplay between dual site phospholambam phosphorylation: insights from genetically altered mouse models. Basic Res Cardiol 97(Suppl 1):I43–I48PubMedGoogle Scholar
  97. 97.
    Mattiazzi A et al (2006) The importance of the Thr17 residue of phospholamban as a phosphorylation site under physiological and pathological conditions. Braz J Med Biol Res 39:563–572CrossRefPubMedGoogle Scholar
  98. 98.
    Ablorh NA et al (2014) Synthetic phosphopeptides enable quantitation of the content and function of the four phosphorylation states of phospholamban in cardiac muscle. J Biol Chem 289(29):397–405Google Scholar
  99. 99.
    Asahi M et al (2000) Physical interactions between phospholamban and sarco(endo)plasmic reticulum Ca2+-ATPases are dissociated by elevated Ca2+, but not by phospholamban phosphorylation, vanadate, or thapsigargin, and are enhanced by ATP. J Biol Chem 275(15):34–38Google Scholar
  100. 100.
    Asahi M et al (1999) 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(32):855–862Google Scholar
  101. 101.
    Karim CB et al (2004) Phospholamban structural dynamics in lipid bilayers probed by a spin label rigidly coupled to the peptide backbone. Proc Natl Acad Sci USA 101(14):437–442Google Scholar
  102. 102.
    Karim CB et al (2006) Phosphorylation-dependent conformational switch in spin-labeled phospholamban bound to SERCA. J Mol Biol 358:1032–1040CrossRefPubMedGoogle Scholar
  103. 103.
    Metcalfe EE, Traaseth NJ, Veglia G (2005) Serine 16 phosphorylation induces an order-to-disorder transition in monomeric phospholamban. Biochemistry 44:4386–4396CrossRefPubMedGoogle Scholar
  104. 104.
    Arkin IT et al (1995) Structural model of the phospholamban ion channel complex in phospholipid membranes. J Mol Biol 248:824–834CrossRefPubMedGoogle Scholar
  105. 105.
    Simmerman HK, Lovelace DE, Jones LR (1989) Secondary structure of detergent-solubilized phospholamban, a phosphorylatable, oligomeric protein of cardiac sarcoplasmic reticulum. Biochim Biophys Acta 997:322–329CrossRefPubMedGoogle Scholar
  106. 106.
    Kim J et al (2015) Dysfunctional conformational dynamics of protein kinase A induced by a lethal mutant of phospholamban hinder phosphorylation. Proc Natl Acad Sci USA 112:3716–3721PubMedPubMedCentralGoogle Scholar
  107. 107.
    Sugita Y et al (2006) Structural changes in the cytoplasmic domain of phospholamban by phosphorylation at Ser16: a molecular dynamics study. Biochemistry 45:11752–11761CrossRefPubMedGoogle Scholar
  108. 108.
    Haghighi K et al (2003) Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human. J Clin Invest 111:869–876CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Young HS, Ceholski DK, Trieber CA (2015) Deception in simplicity: hereditary phospholamban mutations in dilated cardiomyopathy. Biochem Cell Biol 93:1–7CrossRefPubMedGoogle Scholar
  110. 110.
    Schmitt JP et al (2009) Alterations of phospholamban function can exhibit cardiotoxic effects independent of excessive sarcoplasmic reticulum Ca2+-ATPase inhibition. Circulation 119:436–444CrossRefPubMedGoogle Scholar
  111. 111.
    Ha KN et al (2011) Lethal Arg9Cys phospholamban mutation hinders Ca2+-ATPase regulation and phosphorylation by protein kinase A. Proc Natl Acad Sci USA 108:2735–2740CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Gramolini AO et al (2008) Comparative proteomics profiling of a phospholamban mutant mouse model of dilated cardiomyopathy reveals progressive intracellular stress responses. Mol Cell Proteomics 7:519–533CrossRefPubMedGoogle Scholar
  113. 113.
    Abrol N, de Tombe PP, Robia SL (2015) Acute inotropic and lusitropic effects of cardiomyopathic R9C mutation of phospholamban. J Biol Chem 290:7130–7140CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Ceholski DK, Trieber CA, Young HS (2012) Hydrophobic imbalance in the cytoplasmic domain of phospholamban is a determinant for lethal dilated cardiomyopathy. J Biol Chem 287(16):521–529Google Scholar
  115. 115.
    Ceholski DK et al (2012) Lethal, hereditary mutants of phospholamban elude phosphorylation by protein kinase A. J Biol Chem 287(26):596–605Google Scholar
  116. 116.
    van der Zwaag PA et al (2013) Recurrent and founder mutations in the Netherlands-Phospholamban p.Arg14del mutation causes arrhythmogenic cardiomyopathy. Neth Hear J 21:286–293CrossRefGoogle Scholar
  117. 117.
    Haghighi K et al (2012) The human phospholamban Arg14-deletion mutant localizes to plasma membrane and interacts with the Na/K-ATPase. J Mol Cell Cardiol 52:773–782CrossRefPubMedGoogle Scholar
  118. 118.
    Karakikes I et al (2015) Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy. Nat Commun 6:6955CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Te Rijdt WP et al (2016) Phospholamban p.Arg14del cardiomyopathy is characterized by phospholamban aggregates, aggresomes, and autophagic degradation. Histopathology 69:542–550CrossRefGoogle Scholar
  120. 120.
    DeWitt MM et al (2006) Phospholamban R14 deletion results in late-onset, mild, hereditary dilated cardiomyopathy. J Am Coll Cardiol 48:1396–1398CrossRefPubMedGoogle Scholar
  121. 121.
    Luo W et al (1994) Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation. Circ Res 75:401–409CrossRefPubMedGoogle Scholar
  122. 122.
    Abrol N et al (2014) Phospholamban C-terminal residues are critical determinants of the structure and function of the calcium ATPase regulatory complex. J Biol Chem 289(25):855–866Google Scholar
  123. 123.
    Liu GS et al (2015) A novel human R25C-phospholamban mutation is associated with super-inhibition of calcium cycling and ventricular arrhythmia. Cardiovasc Res 107:164–174CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Minamisawa S et al (2003) Mutation of the phospholamban promoter associated with hypertrophic cardiomyopathy. Biochem Biophys Res Commun 304:1–4CrossRefPubMedGoogle Scholar
  125. 125.
    Medin M et al (2007) Mutational screening of phospholamban gene in hypertrophic and idiopathic dilated cardiomyopathy and functional study of the PLN -42 C>G mutation. Eur J Heart Fail 9:37–43CrossRefPubMedGoogle Scholar
  126. 126.
    Haghighi K et al (2008) A human phospholamban promoter polymorphism in dilated cardiomyopathy alters transcriptional regulation by glucocorticoids. Hum Mutat 29:640–647CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Landstrom AP et al (2011) PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing. Am Heart J 161:165–171CrossRefPubMedGoogle Scholar
  128. 128.
    Wawrzynow A et al (1992) Sarcolipin, the “proteolipid” of skeletal muscle sarcoplasmic reticulum, is a unique, amphipathic, 31-residue peptide. Arch Biochem Biophys 298:620–623CrossRefPubMedGoogle Scholar
  129. 129.
    Odermatt A et al (1997) Characterization of the gene encoding human sarcolipin (SLN), a proteolipid associated with SERCA1: absence of structural mutations in five patients with Brody disease. Genomics 45:541–553CrossRefPubMedGoogle Scholar
  130. 130.
    Odermatt A et al (1998) Sarcolipin regulates the activity of SERCA1, the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+-ATPase. J Biol Chem 273(12):360–369Google Scholar
  131. 131.
    Minamisawa S et al (2003) Atrial chamber-specific expression of sarcolipin is regulated during development and hypertrophic remodeling. J Biol Chem 278:9570–9575CrossRefPubMedGoogle Scholar
  132. 132.
    Vangheluwe P et al (2005) Sarcolipin and phospholamban mRNA and protein expression in cardiac and skeletal muscle of different species. Biochem J 389:151–159CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Babu GJ et al (2007) Differential expression of sarcolipin protein during muscle development and cardiac pathophysiology. J Mol Cell Cardiol 43:215–222CrossRefPubMedPubMedCentralGoogle Scholar
  134. 134.
    Asahi M et al (2003) Sarcolipin regulates sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) by binding to transmembrane helices alone or in association with phospholamban. Proc Natl Acad Sci USA 100:5040–5045CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Morita T et al (2008) Interaction sites among phospholamban, sarcolipin, and the sarco(endo)plasmic reticulum Ca(2+)-ATPase. Biochem Biophys Res Commun 369:188–194CrossRefPubMedGoogle Scholar
  136. 136.
    Shaikh SA, Sahoo SK, Periasamy M (2016) Phospholamban and sarcolipin: are they functionally redundant or distinct regulators of the Sarco(Endo)Plasmic Reticulum Calcium ATPase? J Mol Cell Cardiol 91:81–91CrossRefPubMedGoogle Scholar
  137. 137.
    Asahi M et al (2002) Sarcolipin inhibits polymerization of phospholamban to induce superinhibition of sarco(endo)plasmic reticulum Ca2+-ATPases (SERCAs). J Biol Chem 277(26):725–728Google Scholar
  138. 138.
    Hughes E et al (2007) Solid-state NMR and functional measurements indicate that the conserved tyrosine residues of sarcolipin are involved directly in the inhibition of SERCA1. J Biol Chem 282(26):603–613Google Scholar
  139. 139.
    Tupling AR, Asahi M, MacLennan DH (2002) Sarcolipin overexpression in rat slow twitch muscle inhibits sarcoplasmic reticulum Ca2+ uptake and impairs contractile function. J Biol Chem 277(44):740–746Google Scholar
  140. 140.
    Babu GJ et al (2006) Targeted overexpression of sarcolipin in the mouse heart decreases sarcoplasmic reticulum calcium transport and cardiac contractility. J Biol Chem 281:3972–3979CrossRefPubMedGoogle Scholar
  141. 141.
    Bhupathy P et al (2009) Threonine-5 at the N-terminus can modulate sarcolipin function in cardiac myocytes. J Mol Cell Cardiol 47:723–729CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Gramolini AO et al (2006) Cardiac-specific overexpression of sarcolipin in phospholamban null mice impairs myocyte function that is restored by phosphorylation. Proc Natl Acad Sci USA 103:2446–2451CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    Hellstern S et al (2001) Sarcolipin, the shorter homologue of phospholamban, forms oligomeric structures in detergent micelles and in liposomes. J Biol Chem 276(30):845–852Google Scholar
  144. 144.
    Autry JM et al (2011) Oligomeric interactions of sarcolipin and the Ca-ATPase. J Biol Chem 286(31):697–706Google Scholar
  145. 145.
    Gorski PA et al (2013) Sarco(endo)plasmic reticulum calcium ATPase (SERCA) inhibition by sarcolipin is encoded in its luminal tail. J Biol Chem 288:8456–8467CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Gramolini AO et al (2004) Sarcolipin retention in the endoplasmic reticulum depends on its C-terminal RSYQY sequence and its interaction with sarco(endo)plasmic Ca(2+)-ATPases. Proc Natl Acad Sci USA 101(16):807–812Google Scholar
  147. 147.
    Mascioni A et al (2002) Structure and orientation of sarcolipin in lipid environments. Biochemistry 41:475–482CrossRefPubMedGoogle Scholar
  148. 148.
    Buffy JJ et al (2006) Two-dimensional solid-state NMR reveals two topologies of sarcolipin in oriented lipid bilayers. Biochemistry 45:10939–10946CrossRefPubMedGoogle Scholar
  149. 149.
    Becucci L et al (2007) An electrochemical investigation of sarcolipin reconstituted into a mercury-supported lipid bilayer. Biophys J 93:2678–2687CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Becucci L et al (2009) The role of sarcolipin and ATP in the transport of phosphate ion into the sarcoplasmic reticulum. Biophys J 97:2693–2699CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Stefanova HI, East JM, Lee AG (1991) Covalent and non-covalent inhibitors of the phosphate transporter of sarcoplasmic reticulum. Biochim Biophys Acta 1064:321–328CrossRefPubMedGoogle Scholar
  152. 152.
    Stefanova HI et al (1991) Effects of Mg2+ and ATP on the phosphate transporter of sarcoplasmic reticulum. Biochim Biophys Acta 1064:329–334CrossRefPubMedGoogle Scholar
  153. 153.
    Toyoshima C et al (2003) Modeling of the inhibitory interaction of phospholamban with the Ca2+ ATPase. Proc Natl Acad Sci USA 100:467–472CrossRefPubMedPubMedCentralGoogle Scholar
  154. 154.
    Winther AM et al (2013) The sarcolipin-bound calcium pump stabilizes calcium sites exposed to the cytoplasm. Nature 495:265–269CrossRefPubMedGoogle Scholar
  155. 155.
    Toyoshima C et al (2013) Crystal structures of the calcium pump and sarcolipin in the Mg2+-bound E1 state. Nature 495:260–264CrossRefPubMedGoogle Scholar
  156. 156.
    Henderson IM et al (1994) Binding of Ca2+ to the (Ca(2+)-Mg2+)-ATPase of sarcoplasmic reticulum: kinetic studies. Biochem J 297(Pt 3):625–636CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Shanmugam M et al (2011) Decreased sarcolipin protein expression and enhanced sarco(endo)plasmic reticulum Ca2+ uptake in human atrial fibrillation. Biochem Biophys Res Commun 410:97–101CrossRefPubMedPubMedCentralGoogle Scholar
  158. 158.
    Uemura N et al (2004) Down-regulation of sarcolipin mRNA expression in chronic atrial fibrillation. Eur J Clin Investig 34:723–730CrossRefGoogle Scholar
  159. 159.
    Xie LH et al (2012) Ablation of sarcolipin results in atrial remodeling. Am J Phys Cell Physiol 302:C1762–C1771CrossRefGoogle Scholar
  160. 160.
    Pashmforoush M et al (2004) Nkx2-5 pathways and congenital heart disease; loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block. Cell 117:373–386CrossRefPubMedGoogle Scholar
  161. 161.
    Asahi M et al (2004) Cardiac-specific overexpression of sarcolipin inhibits sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2a) activity and impairs cardiac function in mice. Proc Natl Acad Sci USA 101:9199–9204CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Babu GJ et al (2007) Ablation of sarcolipin enhances sarcoplasmic reticulum calcium transport and atrial contractility. Proc Natl Acad Sci USA 104(17):867–872Google Scholar
  163. 163.
    Pant M, Bal NC, Periasamy M (2016) Sarcolipin: a key thermogenic and metabolic regulator in skeletal muscle. Trends Endocrinol Metab 27:881–892CrossRefPubMedPubMedCentralGoogle Scholar
  164. 164.
    Sahoo SK et al (2013) 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 288:6881–6889CrossRefPubMedPubMedCentralGoogle Scholar
  165. 165.
    Bal NC et al (2012) Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals. Nat Med 18:1575–1579CrossRefPubMedPubMedCentralGoogle Scholar
  166. 166.
    Maurya SK et al (2015) Sarcolipin is a key determinant of the basal metabolic rate, and its overexpression enhances energy expenditure and resistance against diet-induced obesity. J Biol Chem 290(10):840–849Google Scholar
  167. 167.
    Zhai J et al (2000) Cardiac-specific overexpression of a superinhibitory pentameric phospholamban mutant enhances inhibition of cardiac function in vivo. J Biol Chem 275(10):538–544Google Scholar
  168. 168.
    Feldman AM et al (1991) Selective gene expression in failing human heart. Quantification of steady-state levels of messenger RNA in endomyocardial biopsies using the polymerase chain reaction. Circulation 83:1866–1872CrossRefPubMedGoogle Scholar
  169. 169.
    Meyer M et al (1995) Alterations of sarcoplasmic reticulum proteins in failing human dilated cardiomyopathy. Circulation 92:778–784CrossRefPubMedGoogle Scholar
  170. 170.
    Dash R et al (2001) Gender influences on sarcoplasmic reticulum Ca2+-handling in failing human myocardium. J Mol Cell Cardiol 33:1345–1353CrossRefPubMedGoogle Scholar
  171. 171.
    del Monte F et al (1999) Restoration of contractile function in isolated cardiomyocytes from failing human hearts by gene transfer of SERCA2a. Circulation 100:2308–2311CrossRefPubMedCentralGoogle Scholar
  172. 172.
    Jaski BE et al (2009) Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial. J Card Fail 15:171–181CrossRefPubMedPubMedCentralGoogle Scholar
  173. 173.
    Jessup M et al (2011) Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure. Circulation 124:304–313CrossRefPubMedPubMedCentralGoogle Scholar
  174. 174.
    Kairouz V et al (2012) Molecular targets in heart failure gene therapy: current controversies and translational perspectives. Ann N Y Acad Sci 1254:42–50CrossRefPubMedPubMedCentralGoogle Scholar
  175. 175.
    Hulot JS, Ishikawa K, Hajjar RJ (2016) Gene therapy for the treatment of heart failure: promise postponed. Eur Heart J 37:1651–1658CrossRefPubMedPubMedCentralGoogle Scholar
  176. 176.
    Kho C et al (2011) SUMO1-dependent modulation of SERCA2a in heart failure. Nature 477:601–605CrossRefPubMedPubMedCentralGoogle Scholar
  177. 177.
    Haghighi K et al (2001) Superinhibition of sarcoplasmic reticulum function by phospholamban induces cardiac contractile failure. J Biol Chem 276(24):145–152Google Scholar
  178. 178.
    Nicolaou P, Kranias EG (2009) Role of PP1 in the regulation of Ca cycling in cardiac physiology and pathophysiology. Front Biosci 14:3571–3585CrossRefGoogle Scholar
  179. 179.
    Ishikawa K et al (2014) Cardiac I-1c overexpression with reengineered AAV improves cardiac function in swine ischemic heart failure. Mol Ther 22:2038–2045CrossRefPubMedPubMedCentralGoogle Scholar
  180. 180.
    Nelson BR et al (2016) A peptide encoded by a transcript annotated as long noncoding RNA enhances SERCA activity in muscle. Science 351:271–275CrossRefPubMedPubMedCentralGoogle Scholar
  181. 181.
    Anderson DM et al (2015) A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell 160:595–606CrossRefPubMedPubMedCentralGoogle Scholar
  182. 182.
    Anderson DM et al (2016) Widespread control of calcium signaling by a family of SERCA-inhibiting micropeptides. Sci Signal 9:ra119CrossRefPubMedPubMedCentralGoogle Scholar
  183. 183.
    Gorski PA, Ceholski DK, Hajjar RJ (2015) Altered myocardial calcium cycling and energetics in heart failure--a rational approach for disease treatment. Cell Metab 21:183–194CrossRefPubMedPubMedCentralGoogle Scholar
  184. 184.
    Krols M, Bultynck G, Janssens S (2016) ER-mitochondria contact sites: a new regulator of cellular calcium flux comes into play. J Cell Biol 214:367–370CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2017

Authors and Affiliations

  • Przemek A. Gorski
    • 1
  • Delaine K. Ceholski
    • 1
  • Howard S. Young
    • 1
  1. 1.Department of BiochemistryUniversity of AlbertaEdmontonCanada

Personalised recommendations