2N99

Solution structure of the SLURP-2, a secreted isoform of Lynx1

Summary for 2N99

• Entry DOI: 10.2210/pdb2n99/pdb
• NMR Information: BMRB: 25887
• Descriptor: Ly-6/neurotoxin-like protein 1 (1 entity in total)
• Functional Keywords: neuromodulator, cell proliferation, three-finger protein, nicotinic acetylcholine receptor, muscarinic acetylcholine receptor, epithelium, keratinocyte, neuropeptide
• Biological source: Homo sapiens (human)
• Cellular location: Isoform 1: Secreted . Isoform 2: Cell membrane ; Lipid-anchor, GPI-anchor . Isoform 3: Secreted: Q9BZG9
• Total number of polymer chains: 1
• Total formula weight: 8163.42

Authors

Paramonov, A.S.,Shenkarev, Z.O.,Lyukmanova, E.N.,Arseniev, A.S. (deposition date: 2015-11-11, release date: 2016-09-21, Last modification date: 2023-06-14)

Primary citation

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.,Kirpichnikov, M.P.
Secreted Isoform of Human Lynx1 (SLURP-2): Spatial Structure and Pharmacology of Interactions with Different Types of Acetylcholine Receptors.
Sci Rep, 6:30698-30698, 2016

PubMed 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.

PubMed: 27485575
DOI: 10.1038/srep30698

Experimental method

SOLUTION NMR