Structure-Function Elucidation of a New α-Conotoxin, MilIA, from Conus milneedwardsi

Cone snail toxins; Conopeptide; Drug development; Electrophysiology; Ion channel diseases; Nicotinic acetylcholine receptor; Article; Conus (snail); Conus milneedwardsi; Xenopus laevis; Amino Acid Sequence; Animals; Conotoxins; Conus Snail; Mutation; Neurotoxins; Nicotinic Antagonists; Oocytes; Patch-Clamp Techniques; Peptides; Receptors, Nicotinic; Recombinant Proteins; Structure-Activity Relationship

Abstract :

[en] The a-Conotoxins are peptide toxins that are found in the venom of marine cone snails and they are potent antagonists of various subtypes of nicotinic acetylcholine receptors (nAChRs). Because nAChRs have an important role in regulating transmitter release, cell excitability, and neuronal integration, nAChR dysfunctions have been implicated in a variety of severe pathologies. We describe the isolation and characterization of α-conotoxin MilIA, the first conopeptide from the venom of Conus milneedwardsi. The peptide was characterized by electrophysiological screening against several types of cloned nAChRs that were expressed in Xenopus laevis oocytes. MilIA, which is a member of the α3/5 family, is an antagonist of muscle type nAChRs with a high selectivity for muscle versus neuronal subtype nAChRs. Several analogues were designed and investigated for their activity in order to determine the key epitopes of MilIA. Native MilIA and analogues both showed activity at the fetal muscle type nAChR. Two single mutations (Met9 and Asn10) allowed for MilIA to strongly discriminate between the two types of muscle nAChRs. Moreover, one analogue, MilIA [∆1,M2R, M9G, N10K, H11K], displayed a remarkable enhanced potency when compared to native peptide. The key residues that are responsible for switching between muscle and neuronal nAChRs preference were elucidated. Interestingly, the same analogue showed a preference for α9α10 nAChRs among the neuronal types. © 2019 by the authors.

Disciplines :

Chemistry

Author, co-author :

Peigneur, S.; Toxicology and Pharmacology, KU Leuven, Campus Gasthuisberg, O & N2, Herestraat 49, P.O. Box 922, Leuven, 3000, Belgium

Devi, P.; Toxicology and Pharmacology, KU Leuven, Campus Gasthuisberg, O & N2, Herestraat 49, P.O. Box 922, Leuven, 3000, Belgium, CSIR-National Institute of Oceanography, Dona Paula, Goa, 403 004, India

Seldeslachts, A.; Toxicology and Pharmacology, KU Leuven, Campus Gasthuisberg, O & N2, Herestraat 49, P.O. Box 922, Leuven, 3000, Belgium

Ravichandran, S.; Center of Advanced Study in Marine Biology, Annamalai University, Parangipettai, Tamil Nadu 608 502, India

Quinton, Loïc ; Université de Liège - ULiège > Département de chimie (sciences) > Chimie biologique

Tytgat, J.; Toxicology and Pharmacology, KU Leuven, Campus Gasthuisberg, O & N2, Herestraat 49, P.O. Box 922, Leuven, 3000, Belgium

Language :

English

Title :

Structure-Function Elucidation of a New α-Conotoxin, MilIA, from Conus milneedwardsi

Publication date :

2019

Journal title :

Marine Drugs

ISSN :

1660-3397

Publisher :

MDPI AG

Volume :

Issue :

Peer reviewed :

Peer Reviewed verified by ORBi

Name of the research project :

PDM/19/164CELSA/17/047EMBO: ESTF7241EMBO

Funders :

KU Leuven - Katholieke Universiteit Leuven [BE]

Available on ORBi :

since 24 June 2020

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Bibliography

Fu, Y.; Li, C.; Dong, S.; Wu, Y.; Zhangsun, D.; Luo, S. Discovery Methodology of Novel Conotoxins from Conus Species. Mar. Drugs 2018, 16, 417. [CrossRef] [PubMed]
Abraham, N.; Lewis, R.J. Neuronal Nicotinic Acetylcholine Receptor Modulators from Cone Snails. Mar. Drugs 2018, 16, 208. [CrossRef] [PubMed]
Giribaldi, J.; Dutertre, S. Alpha-Conotoxins to explore the molecular, physiological and pathophysiological functions of neuronal nicotinic acetylcholine receptors. Neurosci. Lett. 2018, 679, 24–34. [CrossRef] [PubMed]
Turner, M.W.; Marquart, L.A.; Phillips, P.D.; McDougal, O.M. Mutagenesis of alpha-Conotoxins for Enhancing Activity and Selectivity for Nicotinic Acetylcholine Receptors. Toxins 2019, 11, 113. [CrossRef] [PubMed]
Himaya, S.W.A.; Mari, F.; Lewis, R.J. Accelerated proteomic visualization of individual predatory venoms of Conus purpurascens reveals separately evolved predation-evoked venom cabals. Sci. Rep. 2018, 8, 330. [CrossRef]
Kumar, P.S.; Kumar, D.S.; Umamaheswari, S. A perspective on toxicology of Conus venom peptides. Asian Pac. J. Trop. Med. 2015, 8, 337–351. [CrossRef]
Thapa, P.; Zhang, R.Y.; Menon, V.; Bingham, J.P. Native chemical ligation: A boon to peptide chemistry. Molecules 2014, 19, 14461–14483. [CrossRef]
Safavi-Hemami, H.; Brogan, S.E.; Olivera, B.M. Pain therapeutics from cone snail venoms: From Ziconotide to novel non-opioid pathways. J. Proteom. 2019, 190, 12–20. [CrossRef]
Essack, M.; Bajic, V.B.; Archer, J.A. Conotoxins that confer therapeutic possibilities. Mar. Drugs 2012, 10, 1244–1265. [CrossRef]
Bertrand, D.; Terry, A.V., Jr. The wonderland of neuronal nicotinic acetylcholine receptors. Biochem. Pharmacol. 2018, 151, 214–225. [CrossRef]
Hone, A.J.; McIntosh, J.M. Nicotinic acetylcholine receptors in neuropathic and inflammatory pain. FEBS Lett. 2018, 592, 1045–1062. [CrossRef] [PubMed]
Hone, A.J.; Talley, T.T.; Bobango, J.; Melo, C.H.; Hararah, F.; Gajewiak, J.; Christensen, S.; Harvey, P.J.; Craik, D.J.; McIntosh, J.M. Molecular determinants of alpha-conotoxin potency for inhibition of human and rat alpha6beta4 nicotinic acetylcholine receptors. J. Biol. Chem. 2018, 293, 17838–17852. [CrossRef] [PubMed]
Ma, K.G.; Qian, Y.H. Alpha 7 nicotinic acetylcholine receptor and its effects on Alzheimer’s disease. Neuropeptides 2019, 73, 96–106. [CrossRef] [PubMed]
Kaas, Q.; Yu, R.; Jin, A.H.; Dutertre, S.; Craik, D.J. ConoServer: Updated content, knowledge, and discovery tools in the conopeptide database. Nucleic Acids Res. 2012, 40, D325–D330. [CrossRef] [PubMed]
Groebe, D.R.; Gray, W.R.; Abramson, S.N. Determinants involved in the affinity of alpha-conotoxins GI and SI for the muscle subtype of nicotinic acetylcholine receptors. Biochemistry 1997, 36, 6469–6474. [CrossRef] [PubMed]
Luo, S.; McIntosh, J.M. Iodo-alpha-conotoxin MI selectively binds the alpha/delta subunit interface of muscle nicotinic acetylcholine receptors. Biochemistry 2004, 43, 6656–6662. [CrossRef]
McIntosh, J.M.; Azam, L.; Staheli, S.; Dowell, C.; Lindstrom, J.M.; Kuryatov, A.; Garrett, J.E.; Marks, M.J.; Whiteaker, P. Analogs of alpha-conotoxin MII are selective for alpha6-containing nicotinic acetylcholine receptors. Mol. Pharmacol. 2004, 65, 944–952. [CrossRef]
Papineni, R.V.; Sanchez, J.U.; Baksi, K.; Willcockson, I.U.; Pedersen, S.E. Site-specific charge interactions of alpha-conotoxin MI with the nicotinic acetylcholine receptor. J. Biol. Chem. 2001, 276, 23589–23598. [CrossRef]
Kasheverov, I.E.; Utkin, Y.N.; Tsetlin, V.I. Naturally occurring and synthetic peptides acting on nicotinic acetylcholine receptors. Curr. Pharm. Des. 2009, 15, 2430–2452. [CrossRef]
El Hamdaoui, Y.; Wu, X.; Clark, R.J.; Giribaldi, J.; Anangi, R.; Craik, D.J.; King, G.F.; Dutertre, S.; Kaas, Q.; Herzig, V.; et al. Periplasmic Expression of 4/7 alpha-Conotoxin TxIA Analogs in E. coli Favors Ribbon Isomer Formation—Suggestion of a Binding Mode at the alpha7 nAChR. Front. Pharmacol. 2019, 10, 577. [CrossRef]
Almquist, R.G.; Kadambi, S.R.; Yasuda, D.M.; Weitl, F.L.; Polgar, W.E.; Toll, L.R. Paralytic activity of (des-Glu1)conotoxin GI analogs in the mouse diaphragm. Int. J. Pept. Protein Res. 1989, 34, 455–462. [CrossRef] [PubMed]
Bren, N.; Sine, S.M. Hydrophobic pairwise interactions stabilize alpha-conotoxin MI in the muscle acetylcholine receptor binding site. J. Biol. Chem. 2000, 275, 12692–12700. [CrossRef] [PubMed]
Mordvintsev, D.Y.; Polyak, Y.L.; Kuzmine, D.A.; Levtsova, O.V.; Tourleigh, Y.V.; Kasheverov, I.E. A model for short alpha-neurotoxin bound to nicotinic acetylcholine receptor from Torpedo californica. J. Mol. Neurosci. 2006, 30, 71–72. [CrossRef]
Ning, J.; Li, R.; Ren, J.; Zhangsun, D.; Zhu, X.; Wu, Y.; Luo, S. Alanine-Scanning Mutagenesis of alpha-Conotoxin GI Reveals the Residues Crucial for Activity at the Muscle Acetylcholine Receptor. Mar. Drugs 2018, 16, 507. [CrossRef] [PubMed]
Utkin, Y.N.; Kuch, U.; Kasheverov, I.E.; Lebedev, D.S.; Cederlund, E.; Molles, B.E.; Polyak, I.; Ivanov, I.A.; Prokopev, N.A.; Ziganshin, R.H.; et al. Novel long-chain neurotoxins from Bungarus candidus distinguish the two binding sites in muscle-type nicotinic acetylcholine receptors. Biochem. J. 2019, 476, 1285–1302. [CrossRef] [PubMed]
Liu, L.; Chew, G.; Hawrot, E.; Chi, C.; Wang, C. Two potent alpha3/5 conotoxins from piscivorous Conus achatinus. Acta Biochim. Biophys. Sin. (Shanghai) 2007, 39, 438–444. [CrossRef] [PubMed]
Lin, B.; Xiang, S.; Li, M. Residues Responsible for the Selectivity of alpha-Conotoxins for Ac-AChBP or nAChRs. Mar. Drugs 2016, 14, 173. [CrossRef] [PubMed]
Inserra, M.C.; Kompella, S.N.; Vetter, I.; Brust, A.; Daly, N.L.; Cuny, H.; Craik, D.J.; Alewood, P.F.; Adams, D.J.; Lewis, R.J. Isolation and characterization of alpha-conotoxin LsIA with potent activity at nicotinic acetylcholine receptors. Biochem. Pharmacol. 2013, 86, 791–799. [CrossRef] [PubMed]
Ren, J.; Zhu, X.; Xu, P.; Li, R.; Fu, Y.; Dong, S.; Zhangsun, D.; Wu, Y.; Luo, S. d-Amino Acid Substitution of alpha-Conotoxin RgIA Identifies its Critical Residues and Improves the Enzymatic Stability. Mar. Drugs 2019, 17, 142. [CrossRef]
Pucci, L.; Grazioso, G.; Dallanoce, C.; Rizzi, L.; De Micheli, C.; Clementi, F.; Bertrand, S.; Bertrand, D.; Longhi, R.; De Amici, M.; et al. Engineering of alpha-conotoxin MII-derived peptides with increased selectivity for native alpha6beta2* nicotinic acetylcholine receptors. FASEB J. 2011, 25, 3775–3789. [CrossRef]
Mohammadi, S.A.; Christie, M.J. Conotoxin Interactions with α9α10-nAChRs: Is the α9α10-Nicotinic Acetylcholine Receptor an Important Therapeutic Target for Pain Management? Toxins 2015, 7, 3916–3932. [CrossRef] [PubMed]
Dutton, J.L.; Craik, D.J. alpha-Conotoxins: Nicotinic acetylcholine receptor antagonists as pharmacological tools and potential drug leads. Curr. Med. Chem. 2001, 8, 327–344. [CrossRef] [PubMed]
Yu, R.; Kompella, S.N.; Adams, D.J.; Craik, D.J.; Kaas, Q. Determination of the alpha-conotoxin Vc1.1 binding site on the alpha9alpha10 nicotinic acetylcholine receptor. J. Med. Chem. 2013, 56, 3557–3567. [CrossRef] [PubMed]
Zouridakis, M.; Papakyriakou, A.; Ivanov, I.A.; Kasheverov, I.E.; Tsetlin, V.; Tzartos, S.; Giastas, P. Crystal Structure of the Monomeric Extracellular Domain of alpha9 Nicotinic Receptor Subunit in Complex With alpha-Conotoxin RgIA: Molecular Dynamics Insights into RgIA Binding to alpha9alpha10 Nicotinic Receptors. Front. Pharmacol. 2019, 10, 474. [CrossRef] [PubMed]
Bhimani, R.; Anderson, L. Clinical understanding of spasticity: Implications for practice. Rehabil. Res. Pract. 2014, 2014, 279175. [CrossRef]
Peigneur, S.; Cheneval, O.; Maiti, M.; Leipold, E.; Heinemann, S.H.; Lescrinier, E.; Herdewijn, P.; De Lima, M.E.; Craik, D.J.; Schroeder, C.I.; et al. Where cone snails and spiders meet: Design of small cyclic sodium-channel inhibitors. FASEB J. 2019, 33, 3693–3703. [CrossRef]