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Gene Review

PLN  -  phospholamban

Homo sapiens

Synonyms: CMD1P, CMH18, Cardiac phospholamban, PLB
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Disease relevance of PLN


High impact information on PLN

  • A comprehensive discussion is presented of advances in understanding the structure and function of phospholamban (PLB), the principal regulator of the Ca2+-ATPase of cardiac sarcoplasmic reticulum [6].
  • The oligomerization domain of COMP has marked similarities with proposed models of the pentameric transmembrane ion channels in phospholamban and the acetylcholine receptor [7].
  • Impairments in blood circulation that accompany heart failure can be traced, in part, to alterations in the activity of the sarcoplasmic reticulum Ca2+ pump that are induced by its interactions with phospholamban, a reversible inhibitor [8].
  • The phosphorylation of phospholamban is initiated by beta-adrenergic stimulation, identifying phospholamban as an important component in the stimulation of cardiac activity by beta-agonists [9].
  • The structural properties of phospholamban have been studied by mutagenesis, modeling, and spectroscopy, resulting in a new view of the organization of this key molecule in membranes [9].

Chemical compound and disease context of PLN


Biological context of PLN


Anatomical context of PLN


Associations of PLN with chemical compounds

  • Modeling showed that the SLN/SERCA1a complex closely resembles the PLN/SERCA1a complex, but with the luminal end of SLN extending to the loop connecting M1 and M2, where Tyr-29 and Tyr-31 interact with aromatic residues in SERCA1a [16].
  • Elevated Ca(2+) dissociates both PLN and NF-SLN from their complexes with both SERCA1a and SERCA2a, but NF-SLN induced resistance to Ca(2+) dissociation of the PLN.SERCA complex [19].
  • The further addition of vanadate and thapsigargin, both of which stabilize the E(2) conformation, did not diminish binding of PLN to SERCA [20].
  • We recently solved the three-dimensional structure of chemically synthesized, unphosphorylated, monomeric PLN (C41F) by high-resolution nuclear magnetic resonance spectroscopy in chloroform/methanol [21].
  • The amino acid sequence of PLN is highly conserved, and although all species contain asparagine (Asn), human PLN is unique in containing lysine (Lys) at amino acid 27 [22].

Physical interactions of PLN


Regulatory relationships of PLN


Other interactions of PLN

  • These homologous proteins differ at their N and C termini: the C-terminal Met-Leu-Leu in PLN is replaced by Arg-Ser-Tyr-Gln-Tyr in SLN [26].
  • The reduced phosphorylation state of PLB may lead to decreased Ca2+ sensitivity of SERCA2 in failing human myocardium [27].
  • We detected the formation of a Ca(2+)-dependent complex of S100A1 with SERCA2a and PLB in the human myocardium [28].
  • Coexpression of the transmembrane sequence of phospholamban (Met-PLN28-52) with SERCA1a, SERCA2a, and SERCA3 inhibited Ca2+ transport by lowering apparent Ca2+ affinity [29].
  • Replacing Asn34 of PLB in the Leu9 peptide resulted in superinhibition of SERCA [30].

Analytical, diagnostic and therapeutic context of PLN

  • Protein expression of SERCA2a and phospholamban (Western blot) was assessed in a subset of failing trabeculae [15].
  • In related studies, those PLN mutants that gained inhibitory function also increased levels of co-immunoprecipitation of wild-type SERCA1a and those that lost inhibitory function also reduced association, correlating functional interaction sites with physical interaction sites [31].
  • PLB mRNA expression was quantified in human cardiac preparations by Northern blot analysis [32].
  • Protein expression of PLB and the sarcoplasmic Ca(2+)-ATPase (SERCA) was measured in homogenates by quantitative immunoblotting using specific antibodies [32].
  • Human GM and PLB have been produced in an in vitro transcription/translation system and used for co-immunoprecipitation and biosensor experiments [33].


  1. Regulation of sarco(endo)plasmic reticulum Ca2+ adenosine triphosphatase by phospholamban and sarcolipin: implication for cardiac hypertrophy and failure. Asahi, M., Nakayama, H., Tada, M., Otsu, K. Trends Cardiovasc. Med. (2003) [Pubmed]
  2. Ca2+ signalling and muscle disease. MacLennan, D.H. Eur. J. Biochem. (2000) [Pubmed]
  3. Rapid, high-yield expression and purification of Ca2+-ATPase regulatory proteins for high-resolution structural studies. Douglas, J.L., Trieber, C.A., Afara, M., Young, H.S. Protein Expr. Purif. (2005) [Pubmed]
  4. Effects of mutant and antisense RNA of phospholamban on SR Ca(2+)-ATPase activity and cardiac myocyte contractility. He, H., Meyer, M., Martin, J.L., McDonough, P.M., Ho, P., Lou, X., Lew, W.Y., Hilal-Dandan, R., Dillmann, W.H. Circulation (1999) [Pubmed]
  5. Messenger RNA expression and immunological quantification of phospholamban and SR-Ca(2+)-ATPase in failing and nonfailing human hearts. Linck, B., Bokník, P., Eschenhagen, T., Müller, F.U., Neumann, J., Nose, M., Jones, L.R., Schmitz, W., Scholz, H. Cardiovasc. Res. (1996) [Pubmed]
  6. Phospholamban: protein structure, mechanism of action, and role in cardiac function. Simmerman, H.K., Jones, L.R. Physiol. Rev. (1998) [Pubmed]
  7. The crystal structure of a five-stranded coiled coil in COMP: a prototype ion channel? Malashkevich, V.N., Kammerer, R.A., Efimov, V.P., Schulthess, T., Engel, J. Science (1996) [Pubmed]
  8. Phospholamban: a crucial regulator of cardiac contractility. MacLennan, D.H., Kranias, E.G. Nat. Rev. Mol. Cell Biol. (2003) [Pubmed]
  9. Structural perspectives of phospholamban, a helical transmembrane pentamer. Arkin, I.T., Adams, P.D., Brünger, A.T., Smith, S.O., Engelman, D.M. Annual review of biophysics and biomolecular structure. (1997) [Pubmed]
  10. Relaxation of diaphragm muscle. Coirault, C., Chemla, D., Lecarpentier, Y. J. Appl. Physiol. (1999) [Pubmed]
  11. Dietary tyrosine benefits cognitive and psychomotor performance during body cooling. O'brien, C., Mahoney, C., Tharion, W.J., Sils, I.V., Castellani, J.W. Physiol. Behav. (2007) [Pubmed]
  12. Cardiac-specific overexpression of sarcolipin inhibits sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2a) activity and impairs cardiac function in mice. Asahi, M., Otsu, K., Nakayama, H., Hikoso, S., Takeda, T., Gramolini, A.O., Trivieri, M.G., Oudit, G.Y., Morita, T., Kusakari, Y., Hirano, S., Hongo, K., Hirotani, S., Yamaguchi, O., Peterson, A., Backx, P.H., Kurihara, S., Hori, M., MacLennan, D.H. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  13. Phospholamban domain IB forms an interaction site with the loop between transmembrane helices M6 and M7 of sarco(endo)plasmic reticulum Ca2+ ATPases. Asahi, M., Green, N.M., Kurzydlowski, K., Tada, M., MacLennan, D.H. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  14. Characterization of the gene encoding human sarcolipin (SLN), a proteolipid associated with SERCA1: absence of structural mutations in five patients with Brody disease. Odermatt, A., Taschner, P.E., Scherer, S.W., Beatty, B., Khanna, V.K., Cornblath, D.R., Chaudhry, V., Yee, W.C., Schrank, B., Karpati, G., Breuning, M.H., Knoers, N., MacLennan, D.H. Genomics (1997) [Pubmed]
  15. Sarcoplasmic reticulum Ca2+ load in human heart failure. Pieske, B., Maier, L.S., Schmidt-Schweda, S. Basic Res. Cardiol. (2002) [Pubmed]
  16. Sarcolipin regulates sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) by binding to transmembrane helices alone or in association with phospholamban. Asahi, M., Sugita, Y., Kurzydlowski, K., De Leon, S., Tada, M., Toyoshima, C., MacLennan, D.H. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  17. Sarcolipin, the shorter homologue of phospholamban, forms oligomeric structures in detergent micelles and in liposomes. Hellstern, S., Pegoraro, S., Karim, C.B., Lustig, A., Thomas, D.D., Moroder, L., Engel, J. J. Biol. Chem. (2001) [Pubmed]
  18. SR Ca(2+)-ATPase/phospholamban in cardiomyocyte function. Tada, M., Toyofuku, T. J. Card. Fail. (1996) [Pubmed]
  19. Sarcolipin inhibits polymerization of phospholamban to induce superinhibition of sarco(endo)plasmic reticulum Ca2+-ATPases (SERCAs). Asahi, M., Kurzydlowski, K., Tada, M., MacLennan, D.H. J. Biol. Chem. (2002) [Pubmed]
  20. 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. Asahi, M., McKenna, E., Kurzydlowski, K., Tada, M., MacLennan, D.H. J. Biol. Chem. (2000) [Pubmed]
  21. A structural model of the complex formed by phospholamban and the calcium pump of sarcoplasmic reticulum obtained by molecular mechanics. Hutter, M.C., Krebs, J., Meiler, J., Griesinger, C., Carafoli, E., Helms, V. Chembiochem (2002) [Pubmed]
  22. The presence of Lys27 instead of Asn27 in human phospholamban promotes sarcoplasmic reticulum Ca2+-ATPase superinhibition and cardiac remodeling. Zhao, W., Yuan, Q., Qian, J., Waggoner, J.R., Pathak, A., Chu, G., Mitton, B., Sun, X., Jin, J., Braz, J.C., Hahn, H.S., Marreez, Y., Syed, F., Pollesello, P., Annila, A., Wang, H.S., Schultz, J.e.l. .J., Molkentin, J.D., Liggett, S.B., Dorn, G.W., Kranias, E.G. Circulation (2006) [Pubmed]
  23. A leucine zipper stabilizes the pentameric membrane domain of phospholamban and forms a coiled-coil pore structure. Simmerman, H.K., Kobayashi, Y.M., Autry, J.M., Jones, L.R. J. Biol. Chem. (1996) [Pubmed]
  24. Reduced Ca(2+)-sensitivity of SERCA 2a in failing human myocardium due to reduced serin-16 phospholamban phosphorylation. Schwinger, R.H., Münch, G., Bölck, B., Karczewski, P., Krause, E.G., Erdmann, E. J. Mol. Cell. Cardiol. (1999) [Pubmed]
  25. Role of phospholamban in regulating cardiac sarcoplasmic reticulum calcium pump. Ambudkar, I.S., Shamoo, A.E. Membrane biochemistry. (1984) [Pubmed]
  26. Sarcolipin retention in the endoplasmic reticulum depends on its C-terminal RSYQY sequence and its interaction with sarco(endo)plasmic Ca(2+)-ATPases. Gramolini, A.O., Kislinger, T., Asahi, M., Li, W., Emili, A., MacLennan, D.H. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  27. cAMP-dependent protein kinase A-stimulated sarcoplasmic reticulum function in heart failure. Schwinger, R.H., Bölck, B., Münch, G., Brixius, K., Müller-Ehmsen, J., Erdmann, E. Ann. N. Y. Acad. Sci. (1998) [Pubmed]
  28. Ca2+ -dependent interaction of S100A1 with the sarcoplasmic reticulum Ca2+ -ATPase2a and phospholamban in the human heart. Kiewitz, R., Acklin, C., Schäfer, B.W., Maco, B., Uhrík, B., Wuytack, F., Erne, P., Heizmann, C.W. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  29. Phospholamban regulates the Ca2+-ATPase through intramembrane interactions. Kimura, Y., Kurzydlowski, K., Tada, M., MacLennan, D.H. J. Biol. Chem. (1996) [Pubmed]
  30. Rational design of peptide inhibitors of the sarcoplasmic reticulum calcium pump. Afara, M.R., Trieber, C.A., Glaves, J.P., Young, H.S. Biochemistry (2006) [Pubmed]
  31. 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. Asahi, M., Kimura, Y., Kurzydlowski, K., Tada, M., MacLennan, D.H. J. Biol. Chem. (1999) [Pubmed]
  32. Regional expression of phospholamban in the human heart. Bokník, P., Unkel, C., Kirchhefer, U., Kleideiter, U., Klein-Wiele, O., Knapp, J., Linck, B., Lüss, H., Müller, F.U., Schmitz, W., Vahlensieck, U., Zimmermann, N., Jones, L.R., Neumann, J. Cardiovasc. Res. (1999) [Pubmed]
  33. Biophysical interaction between phospholamban and protein phosphatase 1 regulatory subunit GM. Berrebi-Bertrand, I., Souchet, M., Camelin, J.C., Laville, M.P., Calmels, T., Bril, A. FEBS Lett. (1998) [Pubmed]
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