2. Academic Validation
  3. Secreted Isoform of Human Lynx1 (SLURP-2): Spatial Structure and Pharmacology of Interactions with Different Types of Acetylcholine Receptors

Secreted Isoform of Human Lynx1 (SLURP-2): Spatial Structure and Pharmacology of Interactions with Different Types of Acetylcholine Receptors

  • Sci Rep. 2016 Aug 3;6:30698. doi: 10.1038/srep30698.
E N Lyukmanova 1 2,  M A Shulepko 1 2,  Z O Shenkarev 1 2 3,  M L Bychkov 1 2,  A S Paramonov 1 2,  A O Chugunov 1 2,  D S Kulbatskii 1 2,  M Arvaniti 4,  Eva Dolejsi 5,  T Schaer 6,  A S Arseniev 1 3,  R G Efremov 1 7,  M S Thomsen 4,  V Dolezal 5,  D Bertrand 6,  D A Dolgikh 1 2,  M P Kirpichnikov 1 2
Affiliations

Affiliations

  • 1 Lomonosov Moscow State University, Leninskie Gori 1, Moscow 119234, Russian Federation.
  • 2 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Miklukho-Maklaya Street 16/10, Moscow 117997, Russian Federation.
  • 3 Moscow Institute of Physics and Technology, Institutskiy Pereulok 9, Dolgoprudny, Moscow Region 141700, Russian Federation.
  • 4 Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, DK-2100 Copenhagen, Denmark.
  • 5 Institute of Physiology, Academy of Sciences of the Czech Republic (public research institution), Prague, 14220, Czech Republic.
  • 6 HiQScreen Sàrl, 6 rte de Compois, 1222, Vésenaz, Geneva, Switzerland.
  • 7 National Research University Higher School of Economics, Myasnitskaya ul. 20, 101000 Moscow, Russia.
PMID: 27485575 DOI: 10.1038/srep30698
Abstract

Human-secreted Ly-6/uPAR-related protein-2 (SLURP-2) regulates the growth and differentiation of epithelial cells. Previously, the auto/paracrine activity of SLURP-2 was considered to be mediated via its interaction with the α3β2 subtype of the nicotinic acetylcholine receptors (nAChRs). Here, we describe the structure and pharmacology of a recombinant analogue of SLURP-2. Nuclear magnetic resonance spectroscopy revealed a 'three-finger' fold of SLURP-2 with a conserved β-structural core and three protruding loops. Affinity purification using cortical extracts revealed that SLURP-2 could interact with the α3, α4, α5, α7, β2, and β4 nAChR subunits, revealing its broader pharmacological profile. SLURP-2 inhibits acetylcholine-evoked currents at α4β2 and α3β2-nAChRs (IC50 ~0.17 and >3 μM, respectively) expressed in Xenopus oocytes. In contrast, at α7-nAChRs, SLURP-2 significantly enhances acetylcholine-evoked currents at concentrations <1 μM but induces inhibition at higher concentrations. SLURP-2 allosterically interacts with human M1 and M3 muscarinic acetylcholine receptors (mAChRs) that are overexpressed in CHO cells. SLURP-2 was found to promote the proliferation of human oral keratinocytes via interactions with α3β2-nAChRs, while it inhibited cell growth via α7-nAChRs. SLURP-2/mAChRs interactions are also probably involved in the control of keratinocyte growth. Computer modeling revealed possible SLURP-2 binding to the 'classical' orthosteric agonist/antagonist binding sites at α7 and α3β2-nAChRs.

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