{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Benoit MPMH"],"funding":["U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences","U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke","U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)","U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)","NINDS NIH HHS","Simmons Family Foundation","Agouron Institute","NIGMS NIH HHS","NIH HHS"],"pagination":["5530"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11219953"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["15(1)"],"pubmed_abstract":["Mutations in the microtubule-associated motor protein KIF1A lead to severe neurological conditions known as KIF1A-associated neurological disorders (KAND). Despite insights into its molecular mechanism, high-resolution structures of KIF1A-microtubule complexes remain undefined. Here, we present 2.7-3.5 Å resolution structures of dimeric microtubule-bound KIF1A, including the pathogenic P305L mutant, across various nucleotide states. Our structures reveal that KIF1A binds microtubules in one- and two-heads-bound configurations, with both heads exhibiting distinct conformations with tight inter-head connection. Notably, KIF1A's class-specific loop 12 (K-loop) forms electrostatic interactions with the C-terminal tails of both α- and β-tubulin. The P305L mutation does not disrupt these interactions but alters loop-12's conformation, impairing strong microtubule-binding. Structure-function analysis reveals the K-loop and head-head coordination as major determinants of KIF1A's superprocessive motility. Our findings advance the understanding of KIF1A's molecular mechanism and provide a basis for developing structure-guided therapeutics against KAND."],"journal":["Nature communications"],"pubmed_title":["Cryo-EM unveils kinesin KIF1A's processivity mechanism and the impact of its pathogenic variant P305L."],"pmcid":["PMC11219953"],"funding_grant_id":["R01GM147332","S10 OD019994","R01NS114636","SF349247","R01 GM098469","P41 GM103310","GM103310","R01 NS114636","F00316","R01 GM147332","R01GM113164","R01 GM113164"],"pubmed_authors":["Gennerich A","Sosa H","Asenjo AB","Rao L","Benoit MPMH"],"additional_accession":[]},"is_claimable":false,"name":"Cryo-EM unveils kinesin KIF1A's processivity mechanism and the impact of its pathogenic variant P305L.","description":"Mutations in the microtubule-associated motor protein KIF1A lead to severe neurological conditions known as KIF1A-associated neurological disorders (KAND). Despite insights into its molecular mechanism, high-resolution structures of KIF1A-microtubule complexes remain undefined. Here, we present 2.7-3.5 Å resolution structures of dimeric microtubule-bound KIF1A, including the pathogenic P305L mutant, across various nucleotide states. Our structures reveal that KIF1A binds microtubules in one- and two-heads-bound configurations, with both heads exhibiting distinct conformations with tight inter-head connection. Notably, KIF1A's class-specific loop 12 (K-loop) forms electrostatic interactions with the C-terminal tails of both α- and β-tubulin. The P305L mutation does not disrupt these interactions but alters loop-12's conformation, impairing strong microtubule-binding. Structure-function analysis reveals the K-loop and head-head coordination as major determinants of KIF1A's superprocessive motility. Our findings advance the understanding of KIF1A's molecular mechanism and provide a basis for developing structure-guided therapeutics against KAND.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Jul","modification":"2026-05-29T09:57:42.264Z","creation":"2025-04-04T12:21:13.819Z"},"accession":"S-EPMC11219953","cross_references":{"pubmed":["38956021"],"doi":["10.1038/s41467-024-48720-4"]}}