Key residues in the nicotinic acetylcholine receptor β2 subunit contribute to α-conotoxin LvIA binding

Zhangsun, Dongting, Zhu, Xiaopeng, Wu, Yong, Hu, Yuanyan, Kaas, Quentin, Craik, David J., McIntosh, J. Michael and Luo, Sulan (2015) Key residues in the nicotinic acetylcholine receptor β2 subunit contribute to α-conotoxin LvIA binding. The Journal of Biological Chemistry, 290 15: 9855-9862. doi:10.1074/jbc.M114.632646

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Author Zhangsun, Dongting
Zhu, Xiaopeng
Wu, Yong
Hu, Yuanyan
Kaas, Quentin
Craik, David J.
McIntosh, J. Michael
Luo, Sulan
Title Key residues in the nicotinic acetylcholine receptor β2 subunit contribute to α-conotoxin LvIA binding
Journal name The Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2015-04-10
Year available 2015
Sub-type Article (original research)
DOI 10.1074/jbc.M114.632646
Open Access Status File (Publisher version)
Volume 290
Issue 15
Start page 9855
End page 9862
Total pages 8
Place of publication Bethesda MD USA
Publisher American Society for Biochemistry and Molecular Biology
Collection year 2016
Language eng
Formatted abstract
α-Conotoxin LvIA (α-CTx LvIA) is a small peptide from the venom of the carnivorous marine gastropod Conus lividus and is the most selective inhibitor of α3β2 nicotinic acetylcholine receptors (nAChRs) known to date. It can distinguish the α3β2 nAChR subtype from the α6β2* (* indicates the other subunit) and α3β4 nAChR subtypes. In this study, we performed mutational studies to assess the influence of residues of the β2 subunit versus those of the β4 subunit on the binding of α-CTx LvIA. Although two β2 mutations, α3β2[F119Q] and α3β2[T59K], strongly enhanced the affinity of LvIA, the β2 mutation α3β2[V111I] substantially reduced the binding of LvIA. Increased activity of LvIA was also observed when the β2-T59L mutant was combined with the α3 subunit. There were no significant difference in inhibition of α3β2[T59I], α3β2[Q34A], and α3β2[K79A] nAChRs when compared with wild-type α3β2 nAChR. α-CTx LvIA displayed slower off-rate kinetics at α3β2[F119Q] and α3β2[T59K] than at the wild-type receptor, with the latter mutant having the most pronounced effect. Taken together, these data provide evidence that the β2 subunit contributes to α-CTx LvIA binding and selectivity. The results demonstrate that Val111 is critical and facilitates LvIA binding; this position has not previously been identified as important to binding of other 4/7 framework α-conotoxins. Thr59 and Phe119 of the β2 subunit appear to interfere with LvIA binding, and their replacement by the corresponding residues of the β4 subunit leads to increased affinity.
Keyword Docking
Receptor-interacting protein (RIP)
β subunit contribution
α-Conotoxin LvIA
α3β2 nAChR
Mutant α3β2 subtype
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 3 times in Thomson Reuters Web of Science Article | Citations
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Created: Thu, 26 Mar 2015, 14:56:17 EST by Susan Allen on behalf of Institute for Molecular Bioscience