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Recently, there has been a growing concern regarding the impact of the lipid environment on the structural features of the S31N variant. The native symmetry of the M2 tetramer remains controversial. Here we show that S31N M2 persists in a dimer\u2010of\u2010dimers structure in different lipid preparations independent of the amount of solvating lipids up to at least 180 lipids per tetramer. NMR spectra clearly detect the characteristic resonances of the dimer\u2010of\u2010dimers of M2 (residues 18\u201360 or 18\u201362) reconstituted in lipids. NMR\u2010based distance measurements indicate that two isoleucine residues with upfield shifted alpha carbon resonances, typical of extended conformations, are compatible with a particular side\u2010chain rotameric state and helical backbone geometry. These chemical shifts are therefore compatible with the expected native transmembrane helical fold. Symmetry breaking at the pH sensing H37 residues, detected via peak doubling, is a stable feature of S31N M2 based on the reference strain Udorn\/1972(H3N2). By contrast, the spectrum is dramatically altered for Columbia\/2014\/(H3N2) M2, which differs in sequence in the amphipathic helices. This highlights an allosteric coupling between the amphipathic helices and the pH sensing residues.<\/jats:p>","DOI":"10.1002\/chem.202403129","type":"journal-article","created":{"date-parts":[[2024,11,7]],"date-time":"2024-11-07T05:19:17Z","timestamp":1730956757000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Seeing Double: The Persistent Dimer\u2010of\u2010Dimers Structure of Drug Resistant Influenza A M2"],"prefix":"10.1002","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0144-4792","authenticated-orcid":false,"given":"Marianna","family":"Stampolaki","sequence":"first","affiliation":[{"name":"Department of NMR Based Structural Biology Max Planck Institute for Multidisciplinary Sciences  Am Fassberg 11 G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3819-1204","authenticated-orcid":false,"given":"Abel","family":"Cherian Varkey","sequence":"additional","affiliation":[{"name":"Department of NMR Based Structural Biology Max Planck Institute for Multidisciplinary Sciences  Am Fassberg 11 G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3002-0718","authenticated-orcid":false,"given":"Evgeny","family":"Nimerovsky","sequence":"additional","affiliation":[{"name":"Department of NMR Based Structural Biology Max Planck Institute for Multidisciplinary Sciences  Am Fassberg 11 G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5586-9382","authenticated-orcid":false,"given":"Andrei","family":"Leonov","sequence":"additional","affiliation":[{"name":"Department of NMR Based Structural Biology Max Planck Institute for Multidisciplinary Sciences  Am Fassberg 11 G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2041-5740","authenticated-orcid":false,"given":"Stefan","family":"Becker","sequence":"additional","affiliation":[{"name":"Department of NMR Based Structural Biology Max Planck Institute for Multidisciplinary Sciences  Am Fassberg 11 G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3216-9065","authenticated-orcid":false,"given":"Loren B.","family":"Andreas","sequence":"additional","affiliation":[{"name":"Department of NMR Based Structural Biology Max Planck Institute for Multidisciplinary Sciences  Am Fassberg 11 G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,12,4]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00249-013-0925-x"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/v7072781"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201509910"},{"key":"e_1_2_8_4_1","unstructured":"\u00a0"},{"key":"e_1_2_8_5_2","doi-asserted-by":"crossref","unstructured":"J. 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