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Human Siglecs count 14 unique proteins and in all of those the recognition and binding of the sialic acid on the glycan target involves a conserved, or canonical, Arg residue. For a subset of human Siglecs, namely MAG, Siglec-6, and Siglec-11, this Arg appears not to be essential, suggesting that a different binding mechanism may be at play. In this work, we used all-atom molecular dynamics (MD) simulations, binding assays, and mutagenesis to investigate the structural, mechanistic and energetic details of the binding of Siglec-6 to monosialylated gangliosides. Our results show that Siglec-6 relies only partially on its conserved Arg122 for recognition of membrane-bound gangliosides and that it supplements its binding free energy through interactions with the phospholipids in the membrane surrounding the target epitope. We confirmed by mutagenesis assays that the loss of the key residues (Lys 126 and Trp 127) for membrane interaction abrogates binding. These results provide a step-change in our understanding of the diversification of human Siglecs as molecular precision tools to bind specific sialosides by adapting their structure to the biological environment where these are found.<\/jats:p>","DOI":"10.1038\/s42003-026-09609-8","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T14:24:57Z","timestamp":1769610297000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Glycolipid recognition and binding by Siglec-6 hinges on interactions with the cell membrane"],"prefix":"10.1038","volume":"9","author":[{"given":"Silvia","family":"D\u2019Andrea","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward N.","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9274-0759","authenticated-orcid":false,"given":"Duong","family":"Bui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2586-2542","authenticated-orcid":false,"given":"Ojas","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4791-8524","authenticated-orcid":false,"given":"Lara K.","family":"Mahal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3389-7112","authenticated-orcid":false,"given":"John S.","family":"Klassen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4579-1048","authenticated-orcid":false,"given":"Matthew S.","family":"Macauley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2898-7770","authenticated-orcid":false,"given":"Elisa","family":"Fadda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,28]]},"reference":[{"key":"9609_CR1","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1038\/nri2056","volume":"7","author":"PR Crocker","year":"2007","unstructured":"Crocker, P. 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