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The lynx family proteins, a subset of the Ly6\/uPAR superfamily expressed in multiple brain regions, have been shown to bind to nAChRs and modulate their function via allosteric regulation. The binding interactions between lynx and nAChRs, however, have not been systematically quantified and compared. In this work, we characterized the interactions between lynx1 or lynx2 and \u03b13\u03b24\u2010 or \u03b17\u2010nAChRs using single\u2010molecule atomic force microscopy (AFM). The AFM technique allows the quantification of the off\u2010rate of lynx\u2010nAChR binding and of the energetic barrier width between the bound state and transition state, providing a biophysical means to compare the selectivity of lynx proteins for nAChR subtypes. Results indicate that lynx1\u00a0has a marginal preference for \u03b17\u2010 over \u03b13\u03b24\u2010nAChRs. Strikingly, lynx2 exhibits a two order of magnitude stronger affinity for \u03b13\u03b24\u2010 compared to \u03b17\u2010nAChRs. Together, the AFM assay serves as a valuable tool for the biophysical characterization of lynx\u2010nAChR binding affinities. Revealing the differential affinities of lynx proteins for nAChR subtypes will help elucidate how lynx regulates nAChR\u2010dependent functions in the brain, including nicotine addiction and other critical pathways.<\/jats:p>","DOI":"10.1096\/fba.2021-00012","type":"journal-article","created":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T11:31:24Z","timestamp":1630495884000},"page":"1034-1042","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Biophysical characterization of lynx\u2010nicotinic receptor interactions using atomic force microscopy"],"prefix":"10.1096","volume":"3","author":[{"given":"Avani V.","family":"Pisapati","sequence":"first","affiliation":[{"name":"Department of Bioengineering Lehigh University  Bethlehem Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenpeng","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Bioengineering Lehigh University  Bethlehem Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin R.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Lehigh University  Bethlehem Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Griffin","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Lehigh University  Bethlehem Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie Hoffman","family":"Holick","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Lehigh University  Bethlehem Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Whiteaker","sequence":"additional","affiliation":[{"name":"Division of Neurobiology Barrow Neurological Institute, St. Joseph's Hospital and Medical Center Lehigh University  Phoenix Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wonpil","family":"Im","sequence":"additional","affiliation":[{"name":"Department of Bioengineering Lehigh University  Bethlehem Pennsylvania USA"},{"name":"Department of Biological Sciences Lehigh University  Bethlehem Pennsylvania USA"},{"name":"Department of Chemistry Lehigh University  Bethlehem Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8778-595X","authenticated-orcid":false,"given":"X. 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