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Recent high\u2010resolution cryo\u2010EM structures of the KIF1A R350G and R350W mutants bound to microtubules in both nucleotide\u2010free (apo) and AMP\u2010PNP\u2013bound states revealed a salt bridge between KIF1A R350 and \u03b1\u2010tubulin E415 that forms specifically in the open motor domain conformation and is abolished by both substitutions. Single\u2010molecule motility assays further showed that disruption of this conformation\u2010dependent electrostatic interaction increases motor velocity while reducing processivity and microtubule affinity in the apo state. These findings identify a previously unrecognized mechanism regulating KIF1A motility and highlight how subtle changes in motor mechanochemistry can contribute to KAND pathology.<\/jats:p>","DOI":"10.1002\/cm.70163","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T05:12:17Z","timestamp":1781241137000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond Binding Affinity: How a Conformation\u2010Specific Salt Bridge Tunes\n                    <scp>KIF1A<\/scp>\n                    Mechanochemistry"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4953-9202","authenticated-orcid":false,"given":"Abhipsa","family":"Shatarupa","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Gruss\u2010Lipper Biophotonics Center Albert Einstein College of Medicine  Bronx New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7447-1484","authenticated-orcid":false,"given":"Lu","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Gruss\u2010Lipper Biophotonics Center Albert Einstein College of Medicine  Bronx New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8346-5473","authenticated-orcid":false,"given":"Arne","family":"Gennerich","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Gruss\u2010Lipper Biophotonics Center Albert Einstein College of Medicine  Bronx New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0483-5369","authenticated-orcid":false,"given":"Hernando","family":"Sosa","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Gruss\u2010Lipper Biophotonics Center Albert Einstein College of Medicine  Bronx New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e07\u201003\u20100261"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010024\u201048720\u20104"},{"key":"e_1_2_6_4_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.xhgg.2021.100026","article-title":"Genotype and Defects in Microtubule\u2010Based Motility Correlate With Clinical Severity in KIF1A\u2010Associated Neurological Disorder","volume":"2","author":"Boyle L.","year":"2021","journal-title":"Human Genetics and Genomics Advances"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4213"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1905690116"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2016.02.001"},{"key":"e_1_2_6_8_1","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/0092-8674(91)90391-B","article-title":"Kinesin\u2010Related Gene Unc\u2010104 Is Required for Axonal Transport of Synaptic Vesicles in \n                     C. elegans","volume":"65","author":"Hall D. 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