Related ArticlesThe Influenza M2 Ectodomain Regulates the Conformational Equilibria of the Transmembrane Proton Channel: Insights from Solid-State NMR.
Biochemistry. 2016 Aug 29;
Authors: Kwon B, Hong M
Abstract
The influenza M2 protein is the target of the amantadine family of antiviral drugs, and its transmembrane (TM) domain structure and dynamics have been extensively studied. However, little is known about the structure of the highly conserved N-terminal ectodomain, which contains epitopes targeted by influenza vaccines. In this study, we synthesized an M2 construct containing the N-terminal ectodomain and the TM domain, to understand the site-specific conformation and dynamics of the ectodomain and to investigate the ectodomain effect on the TM structure. We incorporated 13C, 15N-labeled residues into both domains and measured their chemical shifts and linewidths using solid-state NMR. The data indicate that the entire ectodomain is unstructured and dynamic, but the motion is slower for residues closer to the TM domain. 13C lineshapes indicate that this ecto-TM construct undergoes fast uniaxial rotational diffusion, similar to the isolated TM peptide, but drug binding increases the motional rates of the TM helix while slowing down the local motion of the ectodomain residues that are close to the TM domain. Moreover, 13C and 15N chemical shifts indicate that the ectodomain shifts the conformational equilibria of the TM residues towards the drug-bound state even in the absence of amantadine, thus providing a molecular structural basis for the lower inhibitory concentration of full-length M2 compared to the ectodomain-truncated M2. We propose that this conformational selection may result from electrostatic repulsion between negatively charged ectodomain residues in the tetrameric protein. Together with the recent study of the M2 cytoplasmic domain, these results show that intrinsically disordered extramembrane domains in membrane proteins can regulate functionally relevant conformation and dynamics of the structurally ordered transmembrane domains.
PMID: 27571210 [PubMed - as supplied by publisher]
Solid-StateNMR Investigation of the Conformation,Proton Conduction, and Hydration of the Influenza B Virus M2 TransmembraneProton Channel
Solid-StateNMR Investigation of the Conformation,Proton Conduction, and Hydration of the Influenza B Virus M2 TransmembraneProton Channel
Jonathan K. Williams, Daniel Tietze, Myungwoon Lee, Jun Wang and Mei Hong
http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jacsat/0/jacsat.ahead-of-print/jacs.6b03142/20160623/images/medium/ja-2016-03142j_0010.gif
Journal of the American Chemical Society
DOI: 10.1021/jacs.6b03142
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http://feeds.feedburner.com/~r/acs/jacsat/~4/CFFUWOoK8Is
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06-24-2016 12:27 AM
[NMR paper] Solid-State NMR Investigation of the Conformation, Proton Conduction, and Hydration of the Influenza B Virus M2 Transmembrane Proton Channel.
Solid-State NMR Investigation of the Conformation, Proton Conduction, and Hydration of the Influenza B Virus M2 Transmembrane Proton Channel.
Related Articles Solid-State NMR Investigation of the Conformation, Proton Conduction, and Hydration of the Influenza B Virus M2 Transmembrane Proton Channel.
J Am Chem Soc. 2016 Jun 10;
Authors: Williams JK, Tietze D, Lee M, Wang J, Hong M
Abstract
Together with the influenza A virus, influenza B virus causes seasonal flu epidemics. The M2 protein of influenza B (BM2) forms a tetrameric...
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06-11-2016 01:09 PM
[NMR paper] Structural Dynamics and Conformational Equilibria of SERCA Regulatory Proteins in Membranes by Solid-State NMR Restrained Simulations.
Structural Dynamics and Conformational Equilibria of SERCA Regulatory Proteins in Membranes by Solid-State NMR Restrained Simulations.
Related Articles Structural Dynamics and Conformational Equilibria of SERCA Regulatory Proteins in Membranes by Solid-State NMR Restrained Simulations.
Biophys J. 2014 Jun 17;106(12):2566-2576
Authors: De Simone A, Mote KR, Veglia G
Abstract
Solid-state NMR spectroscopy is emerging as a powerful approach to determine structure, topology, and conformational dynamics of membrane proteins at the...
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06-19-2014 06:59 PM
Drug-Induced Conformational and Dynamical Changes of the S31N Mutant of the Influenza M2 Proton Channel Investigated by Solid-State NMR
Drug-Induced Conformational and Dynamical Changes of the S31N Mutant of the Influenza M2 Proton Channel Investigated by Solid-State NMR
Jonathan K. Williams, Daniel Tietze, Jun Wang, Yibing Wu, William F. DeGrado and Mei Hong
http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jacsat/0/jacsat.ahead-of-print/ja4041412/aop/images/medium/ja-2013-041412_0011.gif
Journal of the American Chemical Society
DOI: 10.1021/ja4041412
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http://feeds.feedburner.com/~r/acs/jacsat/~4/SJt4vbTURaE
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06-22-2013 01:40 AM
[NMR paper] Drug-Induced Conformational and Dynamical Changes of the S31N Mutant of the Influenza M2 Proton Channel Investigated by Solid-State NMR.
Drug-Induced Conformational and Dynamical Changes of the S31N Mutant of the Influenza M2 Proton Channel Investigated by Solid-State NMR.
Related Articles Drug-Induced Conformational and Dynamical Changes of the S31N Mutant of the Influenza M2 Proton Channel Investigated by Solid-State NMR.
J Am Chem Soc. 2013 Jun 11;
Authors: Williams JK, Tietze D, Wang J, Wu Y, Degrado WF, Hong M
Abstract
The M2 protein of influenza A viruses forms a tetrameric proton channel that is targeted by the amantadine class of antiviral drugs. A S31N mutation in...
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06-14-2013 07:31 PM
[NMR paper] pH-Dependent Conformation, Dynamics, and Aromatic Interaction of*the*Gating Tryptophan Residue of the Influenza M2 Proton Channel from*Solid-State NMR.
pH-Dependent Conformation, Dynamics, and Aromatic Interaction of*the*Gating Tryptophan Residue of the Influenza M2 Proton Channel from*Solid-State NMR.
Related Articles pH-Dependent Conformation, Dynamics, and Aromatic Interaction of*the*Gating Tryptophan Residue of the Influenza M2 Proton Channel from*Solid-State NMR.
Biophys J. 2013 Apr 16;104(8):1698-708
Authors: Williams JK, Zhang Y, Schmidt-Rohr K, Hong M
Abstract
The M2 protein of the influenza virus conducts protons into the virion under external acidic pH. The proton selectivity of...
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04-23-2013 08:37 PM
NMR Detection of pH-Dependent Histidine–Water Proton Exchange Reveals the Conduction Mechanism of a Transmembrane Proton Channel
NMR Detection of pH-Dependent Histidine–Water Proton Exchange Reveals the Conduction Mechanism of a Transmembrane Proton Channel
Fanghao Hu, Klaus Schmidt-Rohr and Mei Hong
http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jacsat/0/jacsat.ahead-of-print/ja2081185/aop/images/medium/ja-2011-081185_0008.gif
Journal of the American Chemical Society
DOI: 10.1021/ja2081185
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http://feeds.feedburner.com/~r/acs/jacsat/~4/C3pPoB5_PR8
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10-22-2011 10:16 AM
[NMR paper] Transmembrane domain of M2 protein from influenza A virus studied by solid-state (15)
Transmembrane domain of M2 protein from influenza A virus studied by solid-state (15)N polarization inversion spin exchange at magic angle NMR.
Related Articles Transmembrane domain of M2 protein from influenza A virus studied by solid-state (15)N polarization inversion spin exchange at magic angle NMR.
Biophys J. 2000 Aug;79(2):767-75
Authors: Song Z, Kovacs FA, Wang J, Denny JK, Shekar SC, Quine JR, Cross TA
The M2 protein from the influenza A virus forms a proton channel in the virion that is essential for infection. This tetrameric protein...