title: DYNC1H1 mutations associated with neurological diseases compromise processivity of dynein-dynactin-cargo adaptor complexes.
abstract: Mutations in the humanDYNC1H1gene are associated with neurological diseases.DYNC1H1encodes the heavy chain of cytoplasmic dynein-1, a 1.4-MDa motor complex that traffics organelles, vesicles, and macromolecules toward microtubule minus ends. The effects of theDYNC1H1mutations on dynein motility, and consequently their links to neuropathology, are not understood. Here, we address this issue using a recombinant expression system for human dynein coupled to single-molecule resolution in vitro motility assays. We functionally characterize 14DYNC1H1mutations identified in humans diagnosed with malformations in cortical development (MCD) or spinal muscular atrophy with lower extremity predominance (SMALED), as well as three mutations that cause motor and sensory defects in mice. Two of the human mutations, R1962C and H3822P, strongly interfere with dynein's core mechanochemical properties. The remaining mutations selectively compromise the processive mode of dynein movement that is activated by binding to the accessory complex dynactin and the cargo adaptor Bicaudal-D2 (BICD2). Mutations with the strongest effects on dynein motility in vitro are associated with MCD. The vast majority of mutations do not affect binding of dynein to dynactin and BICD2 and are therefore expected to result in linkage of cargos to dynein-dynactin complexes that have defective long-range motility. This observation offers an explanation for the dominant effects ofDYNC1H1mutations in vivo. Collectively, our results suggest that compromised processivity of cargo-motor assemblies contributes to human neurological disease and provide insight into the influence of different regions of the heavy chain on dynein motility.
authors.affiliation: Division of Cell Biology, Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.
authors.forename: Ha Thi
authors.initials: HT
authors.lastname: Hoang
authors.affiliation: Division of Structural Studies, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.
authors.forename: Max A
authors.initials: MA
authors.lastname: Schlager
authors.affiliation: Division of Structural Studies, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Carter
authors.affiliation: Division of Cell Biology, Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom; sbullock@mrc-lmb.cam.ac.uk.
authors.forename: Simon L
authors.identifier: 0000-0001-9491-4548
authors.initials: SL
authors.lastname: Bullock
mesh_terms: D000818:Animals; D002460:Cell Line; D056445:Cytoplasmic Dyneins / Q000235:genetics* / Q000378:metabolism*; D000072159:Dynactin Complex / Q000378:metabolism*; D004398:Dyneins / Q000378:metabolism*; D008040:Genetic Linkage / Q000235:genetics; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009422:Nervous System Diseases / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D061987:Sf9 Cells; D013552:Swine
chemical_list: C511240:DYNC1H1 protein, human; D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D056445:Cytoplasmic Dyneins; D004398:Dyneins
keywords: DYNC1H1; cargo adaptor; dynein; neurological disease; processivity