Skip to main content

Advertisement

Springer Nature Link
Log in

Three-finger proteins from the Ly6/uPAR family: Functional diversity within one structural motif

  • Review
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

    We’re sorry, something doesn't seem to be working properly.

    Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Abstract

The discovery in higher animals of proteins from the Ly6/uPAR family, which have structural homology with snake “three-finger” neurotoxins, has generated great interest in these molecules and their role in the functioning of the organism. These proteins have been found in the nervous, immune, endocrine, and reproductive systems of mammals. There are two types of the Ly6/uPAR proteins: those associated with the cell membrane by GPI-anchor and secreted ones. For some of them (Lynx1, SLURP-1, SLURP-2, Lypd6), as well as for snake α-neurotoxins, the target of action is nico- tinic acetylcholine receptors, which are widely represented in the central and peripheral nervous systems, and in many other tissues, including epithelial cells and the immune system. However, the targets of most proteins from the Ly6/uPAR family and the mechanism of their action remain unknown. This review presents data on the structural and functional properties of the Ly6/uPAR proteins, which reveal a variety of functions within a single structural motif.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

a-Bgtx:

a-bungarotoxin

ACh:

acetylcholine

GABA:

gamma-aminobutyric acid

GPI-anchor:

glycophos-phatidylinositol anchor

Ly6:

lymphocyte antigen 6

mAChR:

muscarinic acetylcholine receptor

nAChR:

nicotinic acetyl-choline receptor

tPA:

tissue plasminogen activator

uPAR:

urokinase plasminogen activator receptor

WTX:

nonconven-tional toxin from Naja kaouthia

References

  1. Koh, K., Joiner, W. J., Wu, M. N., Yue, Z., Smith, C. J., and Sehgal, A. (2008) Identification of SLEEPLESS, a sleep-promoting factor, Science, 321, 372–376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ozhan, G., Sezgin, E., Wehner, D., Pfister, A. S., Kuhl, S. J., Kagermeier-Schenk, B., Kuhl, M., Schwille, P., and Weidinger, G. (2013) Lypd6 enhances Wnt/β-catenin signaling by promoting Lrp6 phosphorylation in raft plasma membrane domains, Dev. Cell, 26, 331–345.

    Article  PubMed  Google Scholar 

  3. Da Silva, S. M., Gates, P. B., and Brockes, J. P. (2002) The newt ortholog of CD59 is implicated in proximodistal identity during amphibian limb regeneration, Dev. Cell, 3, 547–555.

    Article  PubMed  Google Scholar 

  4. Fry, B. G., Wuster, W., Kini, R. M., Brusic, V., Khan, A., Venkataraman, D., and Rooney, A. P. (2003) Molecular evolution and phylogeny of elapid snake venom three-finger toxins, J. Mol. Evol., 57, 110–129.

    Article  CAS  PubMed  Google Scholar 

  5. Hruska, M., Keefe, J., Wert, D., Tekinay, A. B., Hulce, J. J., Ibanez-Tallon, I., and Nishi, R. (2009) Prostate stem cell antigen is an endogenous lynx1-like prototoxin that antagonizes alpha7-containing nicotinic receptors and prevents programmed cell death of parasympathetic neurons, J. Neurosci., 29, 14847–14854.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Miwa, J. M., Ibanez-Tallon, I., Crabtree, G. W., Sanchez, R., Sali, A., Role, L. W., and Heintz, N. (1999) Lynx1, an endogenous toxin-like modulator of nicotinic acetylcholine receptors in the mammalian CNS, Neuron, 23, 105–114.

    Article  CAS  PubMed  Google Scholar 

  7. Kini, R. M., and Doley, R. (2010) Structure, function and evolution of three-finger toxins: mini proteins with multiple targets, Toxicon, 56, 855–867.

    Article  CAS  PubMed  Google Scholar 

  8. Loughner, C. L., Bruford, E. A., McAndrews, M. S., Delp, E. E., Swamynathan, S., and Swamynathan, S. K. (2016) Organization, evolution and functions of the human and mouse Ly6/uPAR family genes, Hum. Genom., 10, 10.

    Article  Google Scholar 

  9. Tsetlin, V. I., and Hucho, F. (2004) Snake and snail toxins acting on nicotinic acetylcholine receptors: fundamental aspects and medical applications, FEBS Lett., 557, 9–13.

    Article  CAS  PubMed  Google Scholar 

  10. Lyukmanova, E. N., Shenkarev, Z. O., Schulga, A. A., Ermolyuk, Y. S., Mordvintsev, D. Y., Utkin, Y. N., Shoulepko, M. A., Hogg, R. C., Bertrand, D., Dolgikh, D. A., Tsetlin, V. I., and Kirpichnikov, M. P. (2007) Bacterial expression, NMR, and electrophysiology analysis of chimeric short/long-chain alpha-neurotoxins acting on neuronal nicotinic receptors, J. Biol. Chem., 282, 24784–24791.

    Article  CAS  PubMed  Google Scholar 

  11. Huang, S., Li, S. X., Bren, J., Cheng, K., Gomoto, R., Chen, L., and Sine, S. M. (2013) Complex between α-bun-garotoxin and an α7 nicotinic receptor ligand-binding domain chimaera, Biochem. J., 454, 303–310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Servent, D., Blanchet, G., Mourier, G., Marquer, C., Marcon, E., and Fruchart-Gaillard, C. (2011) Muscarinic toxins, Toxicon, 58, 455–463.

    Article  CAS  PubMed  Google Scholar 

  13. Marquer, C., Fruchart-Gaillard, C., Letellier, G., Marcon, E., Mourier, G., Zinn-Justin, S., Menez, A., Servent, D., and Gilquin, B. (2011) Structural model of ligand-G protein-coupled receptor (GPCR) complex based on experimental double mutant cycle data: MT7 snake toxin bound to dimeric hM1 muscarinic receptor, J. Biol. Chem., 286, 31661–31675.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nirthanan, S., Gopalakrishnakone, P., Gwee, M. C., Khoo, H. E., and Kini, R. M. (2003) Non-conventional toxins from Elapid venoms, Toxicon, 41, 397–407.

    Article  CAS  PubMed  Google Scholar 

  15. Mordvintsev, D. Y., Polyak, Y. L., Rodionov, D. I., Jakubik, J., Dolezal, V., Karlsson, E., Tsetlin, V. I., and Utkin, Y. N. (2009) Weak toxin WTX from Naja kaouthia cobra venom interacts with both nicotinic and muscarinic acetylcholine receptors, FEBS J., 276, 5065–5075.

    Article  CAS  PubMed  Google Scholar 

  16. Lyukmanova, E. N., Shulepko, M. A., Shenkarev, Z. O., Kasheverov, I. E., Chugunov, A. O., Kulbatskii, D. S., Myshkin, M. Y., Utkin, Y. N., Efremov, R. G., Tsetlin, V. I., Arseniev, A. S., Kirpichnikov, M. P., and Dolgikh, D. A. (2016) Central loop of non-conventional toxin WTX from Naja kaouthia is important for interaction with nicotinic acetylcholine receptors, Toxicon, 119, 274–279.

    Article  CAS  PubMed  Google Scholar 

  17. Lyukmanova, E. N., Shenkarev, Z. O., Shulepko, M. A., Paramonov, A. S., Chugunov, A. O., Janickova, H., Dolejsi, E., Dolezal, V., Utkin, Y. N., Tsetlin, V. I., Arseniev, A. S., Efremov, R. G., Dolgikh, D. A., and Kirpichnikov, M. P. (2015) Structural insight into specificity of interactions between nonconventional three-finger weak toxin from Naja kaouthia (WTX) and muscarinic acetylcholine receptors, J. Biol Chem., 290, 23616–23630.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rosso, J. P., Schwarz, J. R., Diaz-Bustamante, M., Ceard, B., Gutierrez, J. M., Kneussel, M., Pongs, O., Bosmans, F., and Bougis, P. E. (2015) MmTX1 and MmTX2 from coral snake venom potently modulate GABAA receptor activity, Proc. Natl. Acad. Sci. USA, 112, E891–900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hannan, S., Mortensen, M., and Smart, T. G. (2015) Snake neurotoxin α-bungarotoxin is an antagonist at native GABA(A) receptors, Neuropharmacology, 93, 28–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kudryavtsev, D. S., Shelukhina, I. V., Son, L. V., Ojomoko, L. O., Kryukova, E. V., Lyukmanova, E. N., Zhmak, M. N., Dolgikh, D. A., Ivanov, I. A., Kasheverov, I. E., Starkov, V. G., Ramerstorfer, J., Sieghart, W., Tsetlin, V. I., and Utkin, Y. N. (2015) Neurotoxins from snake venoms and α-conotoxin ImI inhibit functionally active ionotropic γ-aminobutyric acid (GABA) receptors, J. Biol. Chem., 290, 22747–22758.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Diochot, S., Baron, A., Salinas, M., Douguet, D., Scarzello, S., Dabert-Gay, A. S., Debayle, D., Friend, V., Alloui, A., Lazdunski, M., and Lingueglia, E. (2012) Black mamba venom peptides target acid-sensing ion channels to abolish pain, Nature, 490, 552–555.

    Article  CAS  PubMed  Google Scholar 

  22. Mourier, G., Salinas, M., Kessler, P., Stura, E. A., Leblanc, M., Tepshi, L., Besson, T., Diochot, S., Baron, A., Douguet, D., Lingueglia, E., and Servent, D. (2016) Mambalgin-1 pain-relieving peptide, stepwise solid-phase synthesis, crystal structure, and functional domain for acid-sensing ion channel 1a inhibition, J. Biol. Chem., 291, 2616–2629.

    Article  CAS  PubMed  Google Scholar 

  23. Efremov, R. G., Volynsky, P. E., Nolde, D. E., Dubovskii, P. V., and Arseniev, A. S. (2002) Interaction of cardiotoxins with membranes: a molecular modeling study, Biophys. J., 83, 144–153.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Dubovskii, P. V., Konshina, A. G., and Efremov, R. G. (2014) Cobra cardiotoxins: membrane interactions and pharmacological potential, Curr. Med. Chem., 21, 270–287.

    Article  CAS  PubMed  Google Scholar 

  25. Feofanov, A. V., Sharonov, G. V., Astapova, M. V., Rodionov, D. I., Utkin, Y. N., and Arseniev, A. S. (2005) Cancer cell injury by cytotoxins from cobra venom is mediated through lysosomal damage, Biochem. J., 390, 11–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cervenansky, C., Dajas, F., Harvey, A. L., and Karlsson, E. (1991) in International Encyclopedia of Pharmacology and Therapeutics: Snake Toxins (Harvey, A. L., ed.) Pergamon Press, New York, pp. 303–321.

  27. Bourne, Y., Taylor, P., and Marchot, P. (1995) Acetyl-cholinesterase inhibition by fasciculin: crystal structure of the complex, Cell, 83, 503–512.

    Article  CAS  PubMed  Google Scholar 

  28. Wu, M., Robinson, J. E., and Joiner, W. J. (2014) SLEEP-LESS is a bifunctional regulator of excitability and cholinergic synaptic transmission, Curr. Biol., 24, 621–629.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wu, M., Liu, C. Z., and Joiner, W. J. (2016) Structural analysis and deletion mutagenesis define regions of QUIVER/SLEEPLESS that are responsible for interactions with shaker-type potassium channels and nicotinic acetylcholine receptors, PLoS One, 11, e0148215.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Yang, B., Yao, X., Gu, S., Zhang, Y., Liu, Z., and Zhang, Y. (2010) Selectivity of lynx proteins on insect nicotinic acetylcholine receptors in the brown planthopper, Nilaparvata lugens, Insect Mol. Biol., 19, 283–289.

    Article  CAS  PubMed  Google Scholar 

  31. McNally, J. D., Wu, S. B., Sturgeon, C. M., and Storey, K. B. (2002) Identification and characterization of a novel freezing inducible gene, li16, in the wood frog Rana sylvatica, FASEB J., 16, 902–904.

    CAS  PubMed  Google Scholar 

  32. Kumar, A., Gates, P. B., Czarkwiani, A., and Brockes, J. P. (2015) An orphan gene is necessary for preaxial digit formation during salamander limb development, Nat. Commun., 6, 8684.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Nomura, K., Tanimoto, Y., Hayashi, F., Harada, E., Shan, X. Y., Shionyu, M., Hijikata, A., Shirai, T., Morigaki, K., and Shimamoto, K. (2017) The role of the Prod1 membrane anchor in newt limb regeneration, Angew. Chem. Int. Ed. Engl., 56, 270–274.

    Article  CAS  PubMed  Google Scholar 

  34. Wang, M., Li, L., Guo, Q., Zhang, S., Ji, D., and Li, H. (2016) Identification and expression of a new Ly6 gene cluster in zebrafish Danio rerio, with implications of being involved in embryonic immunity, Fish Shellfish Immunol., 54, 230–240.

    Article  CAS  PubMed  Google Scholar 

  35. Fletcher, C. M., Harrison, R. A., Lachmann, P. J., and Neuhaus, D. (1994) Structure of a soluble, glycosylated form of the human complement regulatory protein CD59, Structure, 2, 185–199.

    Article  CAS  PubMed  Google Scholar 

  36. Parker, C., Omine, M., Richards, S., Nishimura, J., Bessler, M., Ware, R., Hillmen, P., Luzzatto, L., Young, N., Kinoshita, T., Rosse, W., and Socie, G. (2005) Diagnosis and management of paroxysmal nocturnal hemoglobinuria, Blood, 106, 3699–3709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Blasi, F., and Carmeliet, P. (2002) uPAR: a versatile signaling orchestrator, Nat. Rev. Mol. Cell Biol., 3, 932–943.

    Article  CAS  PubMed  Google Scholar 

  38. Su, S. C., Lin, C. W., Yang, W. E., Fan, W. L., and Yang, S. F. (2016) The urokinase-type plasminogen activator (uPA) system as a biomarker and therapeutic target in human malignancies, Expert Opin. Ther. Targets, 20, 551–566.

    Article  CAS  PubMed  Google Scholar 

  39. Huai, Q., Mazar, A. P., Kuo, A., Parry, G. C., Shaw, D. E., Callahan, J., Li, Y., Yuan, C., Bian, C., Chen, L., Furie, B., Furie, B. C., Cines, D. B., and Huang, M. (2006) Structure of human urokinase plasminogen activator in complex with its receptor, Science, 311, 656–659.

    Article  CAS  PubMed  Google Scholar 

  40. Ibanez-Tallon, I., Miwa, J. M., Wang, H. L., Adams, N. C., Crabtree, G. W., Sine, S. M., and Heintz, N. (2002) Novel modulation of neuronal nicotinic acetylcholine receptors by association with the endogenous prototoxin lynx1, Neuron, 33, 893–903.

    Article  CAS  PubMed  Google Scholar 

  41. Demars, M. P., and Morishita, H. (2014) Cortical parvalbumin and somatostatin GABA neurons express distinct endogenous modulators of nicotinic acetylcholine receptors, Mol. Brain, 7, 75–79.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Nichols, W. A., Henderson, B. J., Yu, C., Parker, R. L., Richards, C. I., Lester, H. A., and Miwa, J. M. (2014) Lynx1 shifts α4β2 nicotinic receptor subunit stoichiometry by affecting assembly in the endoplasmic reticulum, J. Biol. Chem., 289, 31423–31432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Miwa, J. M., Stevens, T. R., King, S. L., Caldarone, B. J., Ibanez-Tallon, I., Xiao, C., Fitzsimonds, R. M., Pavlides, C., Lester, H. A., Picciotto, M. R., and Heintz, N. (2006) The prototoxin lynx1 acts on nicotinic acetylcholine receptors to balance neuronal activity and survival in vivo, Neuron, 51, 587–600.

    Article  CAS  PubMed  Google Scholar 

  44. Miwa, J. M., and Walz, A. (2012) Enhancement in motor learning through genetic manipulation of the Lynx1 gene, PLoS One, 7, e43302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kobayashi, A., Parker, R. L., Wright, A. P., Brahem, H., Ku, P., Oliver, K. M., Walz, A., Lester, H. A., and Miwa, J. M. (2014) Lynx1 supports neuronal health in the mouse dorsal striatum during aging: an ultrastructural investigation, J. Mol. Neurosci., 53, 525–536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Morishita, H., Miwa, J. M., Heintz, N., and Hensch, T. K. (2010) Lynx1, a cholinergic brake, limits plasticity in adult visual cortex, Science, 330, 1238–1240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bukhari, N., Burman, P. N., Hussein, A., Demars, M. P., Sadahiro, M., Brady, D. M., Tsirka, S. E., Russo, S., and Morishita, H. (2015) Unmasking proteolytic activity for adult visual cortex plasticity by the removal of Lynx1, J. Neurosci., 35, 12693–12702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sajo, M., Ellis-Davies, G., and Morishita, H. (2016) Lynx1 limits dendritic spine turnover in the adult visual cortex, J. Neurosci., 36, 9472–9478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Shulepko, M. A., Lyukmanova, E. N., Kasheverov, I. E., Dolgikh, D. A., Tsetlin, V. I., and Kirpichnikov, M. P. (2011) Bacterial expression of the water-soluble domain of lynx1, an endogenous neuromodulator of human nicotinic receptors, Russ. J. Bioorg. Chem., 37, 609–615.

    Article  CAS  Google Scholar 

  50. Lyukmanova, E. N., Shenkarev, Z. O., Shulepko, M. A., Mineev, K. S., D’Hoedt, D., Kasheverov, I. E., Filkin, S. Y., Krivolapova, A. P., Janickova, H., Dolezal, V., Dolgikh, D. A., Arseniev, A. S., Bertrand, D., Tsetlin, V. I., and Kirpichnikov, M. P. (2011) NMR structure and action on nicotinic acetylcholine receptors of water-soluble domain of human LYNX1, J. Biol. Chem., 286, 10618–10627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lyukmanova, E. N., Shulepko, M. A., Buldakova, S. L., Kasheverov, I. E., Shenkarev, Z. O., Reshetnikov, R. V., Filkin, S. Y., Kudryavtsev, D. S., Ojomoko, L. O., Kryukova, E. V., Dolgikh, D. A., Kirpichnikov, M. P., Bregestovski, P. D., and Tsetlin, V. I. (2013) Ws-LYNX1 residues important for interaction with muscle-type and/or neuronal nicotinic receptors, J. Biol. Chem., 288, 15888–15899.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Taly, A., Corringer, P. J., Guedin, D., Lestage, P., and Changeux, J. P. (2009) Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system, Nat. Rev. Drug Discov., 8, 733–750.

    Article  CAS  PubMed  Google Scholar 

  53. Thomsen, M. S., Cinar, B., Jensen, M. M., Lyukmanova, E. N., Shulepko, M. A., Tsetlin, V., Klein, A. B., and Mikkelsen, J. D. (2014) Expression of the Ly-6 family proteins Lynx1 and Ly6H in the rat brain is compartmentalized, cell-type specific, and developmentally regulated, Brain Struct. Funct., 219, 1923–1934.

    Article  CAS  PubMed  Google Scholar 

  54. Thomsen, M. S., Arvaniti, M., Jensen, M. M., Shulepko, M. A., Dolgikh, D. A., Pinborg, L. H., Hartig, W., Lyukmanova, E. N., and Mikkelsen, J. D. (2016) Lynx1 and Aβ1-42 bind competitively to multiple nicotinic acetylcholine receptor subtypes, Neurobiol. Aging, 46, 13–21.

    Article  CAS  PubMed  Google Scholar 

  55. Fu, X. W., Song, P. F., and Spindel, E. R. (2015) Role of Lynx1 and related Ly6 proteins as modulators of cholinergic signaling in normal and neoplastic bronchial epithelium, Int. Immunopharmacol., 29, 93–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Dessaud, E., Salaun, D., Gayet, O., Chabbert, M., and De Lapeyriere, O. (2006) Identification of lynx2, a novel member of the ly-6/neurotoxin superfamily, expressed in neuronal subpopulations during mouse development, Mol. Cell Neurosci., 31, 232–242.

    Article  CAS  PubMed  Google Scholar 

  57. Tekinay, A. B., Nong, Y., Miwa, J. M., Lieberam, I., Ibanez-Tallon, I., Greengard, P., and Heintz, N. (2009) A role for LYNX2 in anxiety-related behavior, Proc. Natl. Acad. Sci. USA, 106, 4477–4482.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wu, M., Puddifoot, C. A., Taylor, P., and Joiner, W. J. (2015) Mechanisms of inhibition and potentiation of α4β2 nicotinic acetylcholine receptors by members of the Ly6 protein family, J. Biol. Chem., 290, 24509–24518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Darvas, M., Morsch, M., Racz, I., Ahmadi, S., Swandulla, D., and Zimmer, A. (2009) Modulation of the Ca2+ conductance of nicotinic acetylcholine receptors by Lypd6, Eur. Neuropsychopharmacol., 19, 670–681.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Arvaniti, M., Jensen, M. M., Soni, N., Wang, H., Klein, A. B., Thiriet, N., Pinborg, L. H., Muldoon, P. P., Wienecke, J., Imad Damaj, M., Kohlmeier, K. A., Gondre-Lewis, M. C., Mikkelsen, J. D., and Thomsen, M. S. (2016) Functional interaction between Lypd6 and nicotinic acetylcholine receptors, J. Neurochem., 138, 806–820.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zhang, Y., Lang, Q., Li, J., Xie, F., Wan, B., and Yu, L. (2010) Identification and characterization of human LYPD6, a new member of the Ly-6 superfamily, Mol. Biol. Rep., 37, 2055–2062.

    Article  CAS  PubMed  Google Scholar 

  62. Lyukmanova, E. N., Shulepko, M. A., Kudryavtsev, D., Bychkov, M. L., Kulbatskii, D. S., Kasheverov, I. E., Astapova, M. V., Feofanov, A. V., Thomsen, M. S., Mikkelsen, J. D., Shenkarev, Z. O., Tsetlin, V. I., Dolgikh, D. A., and Kirpichnikov M. P. (2016) Human secreted Ly-6/uPAR related protein-1 (SLURP-1) is a selective allosteric antagonist of α7 nicotinic acetylcholine receptor, PLoS One, 11, e0149733.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Ni, J., Lang, Q., Bai, M., Zhong, C., Chen, X., Wan, B., and Yu, L. (2009) Cloning and characterization of a human LYPD7, a new member of the Ly-6 superfamily, Mol. Biol. Rep., 36, 697–703.

    Article  CAS  PubMed  Google Scholar 

  64. Paramonov, A. S., Kulbatskii, D. S., Loktyushov, E. V., Tsarev, A. V., Dolgikh, D. A., Shenkarev, Z. O., Kirpichnikov, M. P., and Lyukmanova, E. N. (2017) Recombinant production and structural study of the human Lypd6 and Lypd6B proteins, Russ. J. Bioorg. Chem., 43, 644–652.

    Google Scholar 

  65. Ochoa, V., George, A. A., Nishi, R., and Whiteaker, P. (2016) The prototoxin LYPD6B modulates heteromeric α3β4-containing nicotinic acetylcholine receptors, but not α7 homomers, FASEB J., 30, 809–816.

    Article  Google Scholar 

  66. Reiter, R. E., Gu, Z., Watabe, T., Thomas, G., Szigeti, K., Davis, E., Wahl, M., Nisitani, S., Yamashiro, J., Le Beau, M. M., Loda, M., and Witte, O. N. (1998) Prostate stem cell antigen: a cell surface marker overexpressed in prostate cancer, Proc. Natl. Acad. Sci. USA, 95, 1735–1740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Jensen, M. M., Arvaniti, M., Mikkelsen, J. D., Michalski, D., Pinborg, L. H., Hartig, W., and Thomsen, M. S. (2015) Prostate stem cell antigen interacts with nicotinic acetylcholine receptors and is affected in Alzheimer’s disease, Neurobiol. Aging, 36, 1629–1638.

    Article  CAS  PubMed  Google Scholar 

  68. Ono, H., Hiraoka, N., Lee, Y. S., Woo, S. M., Lee, W. J., Choi, I. J., Saito, A., Yanagihara, K., Kanai, Y., Ohnami, S., Chiwaki, F., Sasaki, H., Sakamoto, H., Yoshida, T., and Saeki, N. (2012) Prostate stem cell antigen, a presumable organ-dependent tumor suppressor gene, is down-regulated in gallbladder carcinogenesis, Genes Chromosomes Cancer, 51, 30–41.

    Article  CAS  PubMed  Google Scholar 

  69. Moore, M. L., Teitell, M. A., Kim, Y., Watabe, T., Reiter, R. E., Witte, O. N., and Dubey, P. (2008) Deletion of PSCA increases metastasis of TRAMP-induced prostate tumors without altering primary tumor formation, Prostate, 68, 139–151.

    Article  CAS  PubMed  Google Scholar 

  70. Arredondo, J., Chernyavsky, A. I., and Grando, S. A. (2007) SLURP-1 and -2 in normal, immortalized and malignant oral keratinocytes, Life Sci., 80, 2243–2247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Arredondo, J., Chernyavsky, A. I., Webber, R. J., and Grando, S. A. (2005) Biological effects of SLURP-1 on human keratinocytes, J. Invest. Dermatol., 125, 1236–1241.

    Article  CAS  PubMed  Google Scholar 

  72. Chernyavsky, A. I., Kalantari-Dehaghi, M., Phillips, C., Marchenko, S., and Grando, S. A. (2012) Novel cholinergic peptides SLURP-1 and -2 regulate epithelialization of cutaneous and oral wounds, Wound Rep. Regen., 20, 103–113.

    Article  Google Scholar 

  73. Perez, C., and Khachemoune, A. (2016) Mal de Meleda: a focused review, Am. J. Clin. Dermatol., 17, 63–70.

    Article  PubMed  Google Scholar 

  74. Allan, C. M., Procaccia, S., Tran, D., Tu, Y., Barnes, R. H., 2nd, Larsson, M., Allan, B. B., Young, L. C., Hong, C., Tontonoz, P., Fong, L. G., Young, S. G., and Beigneux, A. P. (2016) Palmoplantar keratoderma in Slurp2-deficient mice, J. Invest. Dermatol., 136, 436–443.

    Article  CAS  PubMed  Google Scholar 

  75. Tsuji, H., Okamoto, K., Matsuzaka, Y., Iizuka, H., Tamiya, G., and Inoko, H. (2003) SLURP-2, a novel member of the human Ly-6 superfamily that is up-regulated in psoriasis vulgaris, Genomics, 81, 26–33.

    Article  CAS  PubMed  Google Scholar 

  76. Pettersson, A., Nylund, G., Khorram-Manesh, A., Nordgren, S., and Delbro, D. S. (2009) Nicotine induced modulation of SLURP-1 expression in human colon cancer cells, Auton. Neurosci., 148, 97–100.

    Article  CAS  PubMed  Google Scholar 

  77. Lyukmanova, E. N., Shulepko, M. A., Bychkov, M. L., Shenkarev, Z. O., Paramonov, A. S., Chugunov, A. O., Arseniev, A. S., Dolgikh, D. A., and Kirpichnikov, M. P. (2014) Human SLURP-1 and SLURP-2 proteins acting on nicotinic acetylcholine receptors reduce proliferation of human colorectal adenocarcinoma HT-29 cells, Acta Naturae, 6, 60–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Moriwaki, Y., Yoshikawa, K., Fukuda, H., Fujii, Y. X., Misawa, H., and Kawashima, K. (2007) Immune system expression of SLURP-1 and SLURP-2, two endogenous nicotinic acetylcholine receptor ligands, Life Sci., 80, 2365–2368.

    Article  CAS  PubMed  Google Scholar 

  79. Moriwaki, Y., Watanabe, Y., Shinagawa, T., Kai, M., Miyazawa, M., Okuda, T., Kawashima, K., Yabashi, A., Waguri, S., and Misawa, H. (2009) Primary sensory neuronal expression of SLURP-1, an endogenous nicotinic acetylcholine receptor ligand, Neurosci. Res., 64, 403–412.

    Article  CAS  PubMed  Google Scholar 

  80. Chernyavsky, A. I., Arredondo, J., Galitovskiy, V., Qian, J., and Grando, S. A. (2010) Upregulation of nuclear factor-kappaB expression by SLURP-1 is mediated by alpha7-nicotinic acetylcholine receptor and involves both ionic events and activation of protein kinases, Am. J. Physiol. Cell Physiol., 299, 903–911.

    Article  Google Scholar 

  81. Arredondo, J., Chernyavsky, A. I., Jolkovsky, D. L., Webber, R. J., and Grando, S. A. (2006) SLURP-2: a novel cholinergic signaling peptide in human mucocutaneous epithelium, J. Cell. Physiol., 208, 238–245.

    Article  CAS  PubMed  Google Scholar 

  82. Lyukmanova, E. N., Shulepko, M. A., Shenkarev, Z. O., Bychkov, M. L., Paramonov, A. S., Chugunov, A. O., Kulbatskii, D. S., Arvaniti, M., Dolejsi, E., Schaer, T., Arseniev, A. S., Efremov, R. G., Thomsen, M. S., Dolezal, V., Bertrand, D., Dolgikh, D. A., and Kirpichnikov, M. P. (2016) Secreted isoform of human Lynx1 (SLURP-2): spatial structure and pharmacology of interactions with different types of acetylcholine receptors, Sci. Rep., 6, 30698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Cachelin, A. B., and Rust, G. (1994) Unusual pharmacology of (+)-tubocurarine with rat neuronal nicotinic acetylcholine receptors containing beta 4 subunits, Mol. Pharmacol., 46, 1168–1174.

    CAS  PubMed  Google Scholar 

  84. Shulepko, M. A., Lyukmanova, E. N., Shenkarev, Z. O., Dubovskii, P. V., Astapova, M. V., Feofanov, A. V., Arseniev, A. S., Utkin, Y. N., Kirpichnikov, M. P., and Dolgikh, D. A. (2017) Towards universal approach for bacterial production of three-finger Ly6/uPAR proteins: case study of cytotoxin I from cobra N. oxiana, Protein Expr. Purif., 130, 13–20.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faculty of Biology, Lomonosov Moscow State University, 119991, Moscow, Russia

    N. A. Vasilyeva, E. V. Loktyushov & E. N. Lyukmanova

  2. Shemyakin−Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997, Moscow, Russia

    N. A. Vasilyeva, E. V. Loktyushov, M. L. Bychkov, Z. O. Shenkarev & E. N. Lyukmanova

  3. Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117485, Moscow, Russia

    N. A. Vasilyeva

Authors
  1. N. A. Vasilyeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. V. Loktyushov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. L. Bychkov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Z. O. Shenkarev
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E. N. Lyukmanova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. N. Lyukmanova.

Additional information

Original Russian Text © N. A. Vasilyeva, E. V. Loktyushov, M. L. Bychkov, Z. O. Shenkarev, E. N. Lyukmanova, 2017, published in Uspekhi Biologicheskoi Khimii, 2017, Vol. 57, pp. 303-330.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vasilyeva, N.A., Loktyushov, E.V., Bychkov, M.L. et al. Three-finger proteins from the Ly6/uPAR family: Functional diversity within one structural motif. Biochemistry Moscow 82, 1702–1715 (2017). https://doi.org/10.1134/S0006297917130090

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297917130090

Keywords

Search

Navigation