HGNC Approved Gene Symbol: SLN
Cytogenetic location: 11q22.3 Genomic coordinates (GRCh38): 11:107,707,378-107,712,056 (from NCBI)
Sarcolipin (SLN) is a low molecular weight protein that copurifies with the fast-twitch skeletal muscle sarcoplasmic reticulum Ca(2+) ATPase (ATP2A1; 108730). Odermatt et al. (1997) isolated genomic DNA and cDNA encoding human SLN. Human, rabbit, and mouse cDNAs encode a protein of 31 amino acids. Homology of SLN with phospholamban (PLN; 172405) suggests that the first 7 hydrophilic amino acids are cytoplasmic, the next 19 hydrophobic amino acids form a single transmembrane helix, and the last 5 hydrophilic amino acids are luminal. The cytoplasmic and transmembrane sequences are not well conserved among the 3 species, but the luminal sequence is highly conserved. Like ATP2A1, SLN is highly expressed in rabbit fast-twitch skeletal muscle, but it is expressed to a lower extent in slow-twitch muscle and to an even lower extent in cardiac muscle, where ATP2A2 (108740) and PLN are highly expressed. It is expressed in only trace amounts in pancreas and prostate.
Asahi et al. (2004) generated mice with cardiac-specific overexpression of epitope-tagged rabbit Sln. Overexpression of Sln decreased the apparent affinity of Serca2a (ATP2A2) for calcium in transgenic hearts. The mice had altered calcium currents, impaired cardiac contractility with altered tension and relaxation times, and ventricular hypertrophy. Coimmunoprecipitation indicated that overexpressed Sln bound both Serca2a and Pln, forming a ternary complex. The results suggested that Sln overexpression inhibits Serca2a through stabilization of Serca2a-Pln interaction and through inhibition of Pln phosphorylation. Asahi et al. (2004) concluded that inhibition of Serca2a impairs contractility and calcium cycling, but responsiveness to beta-adrenergic agonists may prevent progression to heart failure.
By pairwise testing of fluorescence-labeled proteins, Phillips et al. (2023) showed that different SERCA-modulating membrane micropeptides, including SLN, formed heterooligomers with varying affinities. Moreover, each micropeptide also assembled into homooligomers, but the homooligomers did not interact with SERCA. The affinities of heterooligomerization of micropeptides depended on whether they were the minority or majority species, and SERCA interaction with individual monomeric micropeptides competed with micropeptide-micropeptide interactions. Analysis of SLN-ELN (SMIM6; 620531) oligomer formation revealed that an ELN-SLN heterodimer containing a single acceptor formed first at low micropeptide concentration and proceeded to higher order heterooligomers when the concentration increased.
Odermatt et al. (1997) stated that the SLN and PLN genes resemble each other in having 2 small exons, with their coding sequences lying in exon 2, and a large intron separating the 2 segments.
Odermatt et al. (1997) mapped the SLN gene to 11q22-q23.
Asahi et al. (2004) generated mice with cardiac-specific overexpression of epitope-tagged rabbit sarcolipin. Overexpression of Sln decreased the apparent affinity of Serca2a for calcium in transgenic hearts. Calcium currents were altered, there was impaired cardiac contractility with altered tension and relaxation times, and ventricular hypertrophy. Coimmunoprecipitation indicated that overexpressed Sln bound both Serca2a and phospholamban in a ternary complex. Sln overexpression inhibited Serca2a through stabilization of Serca2a-Pln interaction and through inhibition of Pln phosphorylation. Asahi et al. (2004) concluded that inhibition of Serca2a impaired contractility and calcium cycling, but responsiveness to beta-adrenergic agonists may have prevented progression to heart failure.
Crystal Structure
Toyoshima et al. (2013) described the crystal structure of native Serca1a from rabbit in the E1-Mg(2+) state at 3.0-angstrom resolution in addition to crystal structures of Serca1a in E2 free from exogenous inhibitors, and addressed the structural basis of the activation signal for phosphoryl transfer. Unexpectedly, sarcolipin, a small regulatory membrane protein of Ca(2+)-ATPase, is bound, stabilizing the E1-Mg(2+) state. Sarcolipin is a close homolog of phospholamban (172405), which is a critical mediator of beta-adrenergic signal in calcium regulation in heart and seems to play an important role in muscle-based thermogenesis. Toyoshima et al. (2013) also determined the crystal structure of recombinant SERCA1a devoid of sarcolipin, and described the structural basis of inhibition by sarcolipin/phospholamban.
Winther et al. (2013) reported the crystal structure of rabbit Serca1a in complex with sarcolipin at 3.1-angstrom resolution. The regulatory sarcolipin traps the Ca(2+)-ATPase in a previously undescribed E1 state, with exposure of the Ca(2+) sites through an open cytoplasmic pathway stabilized by Mg(2+). This structure suggests a mechanism for selective Ca(2+) loading and activation of SERCA, and provides insight into how sarcolipin and phospholamban inhibition arises from stabilization of this E1 intermediate state without bound Ca(2+).
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. Cardiac-specific overexpression of sarcolipin inhibits sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA2a) activity and impairs cardiac function in mice. Proc. Nat. Acad. Sci. 101: 9199-9204, 2004. [PubMed: 15201433] [Full Text: https://doi.org/10.1073/pnas.0402596101]
Odermatt, A., Taschner, P. E. M., 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. 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: 541-553, 1997. [PubMed: 9367679] [Full Text: https://doi.org/10.1006/geno.1997.4967]
Phillips, T. A., Hauck, G. T., Pribadi, M. P., Cho, E. E., Cleary, S. R., Robia, S. L. Micropeptide hetero-oligomerization adds complexity to the calcium pump regulatory network. Biophys. J. 122: 301-309, 2023. [PubMed: 36523160] [Full Text: https://doi.org/10.1016/j.bpj.2022.12.014]
Toyoshima, C., Iwasawa, S., Ogawa, H., Hirata, A., Tsueda, J., Inesi, G. Crystal structures of the calcium pump and sarcolipin in the Mg(2+)-bound E1 state. Nature 495: 260-264, 2013. [PubMed: 23455422] [Full Text: https://doi.org/10.1038/nature11899]
Winther, A.-M. L., Bublitz, M., Karlsen, J. L., Moller, J. V., Hansen, J. B., Nissen, P., Buch-Pedersen, M. J. The sarcolipin-bound calcium pump stabilizes calcium sites exposed to the cytoplasm. Nature 495: 265-269, 2013. [PubMed: 23455424] [Full Text: https://doi.org/10.1038/nature11900]