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Structural Influences

Title: Structural Influences: Cholesterol, Drug, and Proton Binding to Full-Length Influenza A M2 Protein.
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Name(s): Ekanayake, E Vindana, author
Fu, Riqiang, author
Cross, Timothy A, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2016-03-29
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: The structure and functions of the M2 protein from Influenza A are sensitive to pH, cholesterol, and the antiinfluenza drug Amantadine. This is a tetrameric membrane protein of 97 amino-acid residues that has multiple functions, among them as a proton-selective channel and facilitator of viral budding, replacing the need for the ESCRT proteins that other viruses utilize. Here, various amino-acid-specific-labeled samples of the full-length protein were prepared and mixed, so that only interresidue (13)C-(13)C cross peaks between two differently labeled proteins representing interhelical interactions are observed. This channel is activated at slightly acidic pH values in the endosome when the His(37) residues in the middle of the transmembrane domain take on a +2 or +3 charged state. Changes observed here in interhelical distances in the N-terminus can be accounted for by modest structural changes, and no significant changes in structure were detected in the C-terminal portion of the channel upon activation of the channel. Amantadine, which blocks proton conductance by binding in the aqueous pore near the N-terminus, however, significantly modifies the tetrameric structure on the opposite side of the membrane. The interactions between the juxtamembrane amphipathic helix of one monomer and its neighboring monomer observed in the absence of drug are disrupted in its presence. However, the addition of cholesterol prevents this structural disruption. In fact, strong interactions are observed between cholesterol and residues in the amphipathic helix, accounting for cholesterol binding adjacent to a native palmitoylation site and near to an interhelix crevice that is typical of cholesterol binding sites. The resultant stabilization of the amphipathic helix deep in the bilayer interface facilitates the bilayer curvature that is essential for viral budding.
Identifier: FSU_pmch_27028648 (IID), 10.1016/j.bpj.2015.11.3529 (DOI), PMC4816700 (PMCID), 27028648 (RID), 27028648 (EID), S0006-3495(16)00152-1 (PII)
Grant Number: R01 AI023007, AI R01-023007
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816700.
Subject(s): Amantadine/metabolism
Amino Acid Sequence
Cholesterol/metabolism
Hydrogen-Ion Concentration
Influenza A virus/metabolism
Protein Domains
Protein Structure, Secondary
Protons
Viral Matrix Proteins/chemistry
Viral Matrix Proteins/metabolism
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_27028648
Owner Institution: FSU
Is Part Of: Biophysical journal.
1542-0086
Issue: iss. 6, vol. 110

Choose the citation style.
Ekanayake, E. V., Fu, R., & Cross, T. A. (2016). Structural Influences: Cholesterol, Drug, and Proton Binding to Full-Length Influenza A M2 Protein. Biophysical Journal. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_27028648