2n99: Difference between revisions
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==Solution structure of the SLURP-2, a secreted isoform of Lynx1== | |||
<StructureSection load='2n99' size='340' side='right' caption='[[2n99]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2n99]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2N99 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2N99 FirstGlance]. <br> | |||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2n99 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2n99 OCA], [http://pdbe.org/2n99 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2n99 RCSB], [http://www.ebi.ac.uk/pdbsum/2n99 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2n99 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/LYNX1_HUMAN LYNX1_HUMAN]] Acts in different tissues through interaction to nicotinic acetylcholine receptors (nAChRs). In brain, isoform 2 modulates functional properties of nAChRs to prevent excessive excitation, and hence neurodegeneration. Enhances desensitization by increasing both the rate and extent of desensitization of alpha(4)beta(2) nAChRs and slowing recovery from desensitization. Promotes large amplitude ACh-evoked currents through alpha(4)beta(2) nAChRs (By similarity). Prevents plasticity in the primary visual cortex late in life (By similarity). In keratinocytes, isoform 3 delays differentiation and prevents apoptosis.<ref>PMID:16575903</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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 alpha3beta2 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 beta-structural core and three protruding loops. Affinity purification using cortical extracts revealed that SLURP-2 could interact with the alpha3, alpha4, alpha5, alpha7, beta2, and beta4 nAChR subunits, revealing its broader pharmacological profile. SLURP-2 inhibits acetylcholine-evoked currents at alpha4beta2 and alpha3beta2-nAChRs (IC50 ~0.17 and >3 muM, respectively) expressed in Xenopus oocytes. In contrast, at alpha7-nAChRs, SLURP-2 significantly enhances acetylcholine-evoked currents at concentrations <1 muM 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 alpha3beta2-nAChRs, while it inhibited cell growth via alpha7-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 alpha7 and alpha3beta2-nAChRs. | |||
Secreted Isoform of Human Lynx1 (SLURP-2): Spatial Structure and Pharmacology of Interactions with Different Types of Acetylcholine Receptors.,Lyukmanova EN, Shulepko MA, Shenkarev ZO, Bychkov ML, Paramonov AS, Chugunov AO, Kulbatskii DS, Arvaniti M, Dolejsi E, Schaer T, Arseniev AS, Efremov RG, Thomsen MS, Dolezal V, Bertrand D, Dolgikh DA, Kirpichnikov MP Sci Rep. 2016 Aug 3;6:30698. doi: 10.1038/srep30698. PMID:27485575<ref>PMID:27485575</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Paramonov, A | <div class="pdbe-citations 2n99" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
</StructureSection> | |||
[[Category: Arseniev, A S]] | |||
[[Category: Lyukmanova, E N]] | |||
[[Category: Paramonov, A S]] | |||
[[Category: Shenkarev, Z O]] | |||
[[Category: Cell proliferation]] | |||
[[Category: Epithelium]] | |||
[[Category: Keratinocyte]] | |||
[[Category: Muscarinic acetylcholine receptor]] | |||
[[Category: Neuromodulator]] | |||
[[Category: Neuropeptide]] | |||
[[Category: Nicotinic acetylcholine receptor]] | |||
[[Category: Three-finger protein]] | |||
Revision as of 16:42, 21 September 2016
Solution structure of the SLURP-2, a secreted isoform of Lynx1Solution structure of the SLURP-2, a secreted isoform of Lynx1
Structural highlights
Function[LYNX1_HUMAN] Acts in different tissues through interaction to nicotinic acetylcholine receptors (nAChRs). In brain, isoform 2 modulates functional properties of nAChRs to prevent excessive excitation, and hence neurodegeneration. Enhances desensitization by increasing both the rate and extent of desensitization of alpha(4)beta(2) nAChRs and slowing recovery from desensitization. Promotes large amplitude ACh-evoked currents through alpha(4)beta(2) nAChRs (By similarity). Prevents plasticity in the primary visual cortex late in life (By similarity). In keratinocytes, isoform 3 delays differentiation and prevents apoptosis.[1] Publication Abstract from PubMedHuman-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 alpha3beta2 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 beta-structural core and three protruding loops. Affinity purification using cortical extracts revealed that SLURP-2 could interact with the alpha3, alpha4, alpha5, alpha7, beta2, and beta4 nAChR subunits, revealing its broader pharmacological profile. SLURP-2 inhibits acetylcholine-evoked currents at alpha4beta2 and alpha3beta2-nAChRs (IC50 ~0.17 and >3 muM, respectively) expressed in Xenopus oocytes. In contrast, at alpha7-nAChRs, SLURP-2 significantly enhances acetylcholine-evoked currents at concentrations <1 muM 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 alpha3beta2-nAChRs, while it inhibited cell growth via alpha7-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 alpha7 and alpha3beta2-nAChRs. Secreted Isoform of Human Lynx1 (SLURP-2): Spatial Structure and Pharmacology of Interactions with Different Types of Acetylcholine Receptors.,Lyukmanova EN, Shulepko MA, Shenkarev ZO, Bychkov ML, Paramonov AS, Chugunov AO, Kulbatskii DS, Arvaniti M, Dolejsi E, Schaer T, Arseniev AS, Efremov RG, Thomsen MS, Dolezal V, Bertrand D, Dolgikh DA, Kirpichnikov MP Sci Rep. 2016 Aug 3;6:30698. doi: 10.1038/srep30698. PMID:27485575[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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