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DTSTART:19960101T000000 END:STANDARD BEGIN:STANDARD TZNAME:GMT TZOFFSETFROM:+0100 TZOFFSETTO:+0000 DTSTART:19961027T020000 RRULE:FREQ=YEARLY;BYMONTH=10;BYDAY=-1SU END:STANDARD END:VTIMEZONE BEGIN:VEVENT DTSTAMP:20260508T084610Z DTSTART;VALUE=DATE-TIME:20230329T130000 DTEND;VALUE=DATE-TIME:20230329T140000 SUMMARY:BMS Seminar: The hereditary spastic paraplegia-associated kinesin KIF1C drives bidirectional intracellular transport\, Professor Anne Str aube\, Division of Biomedical Sciences\, ÌÇÐÄTV Medical School TZID:Europe/London UID:20230329-8a17841a837f52ba01838d6d81ed5ea2@warwick.ac.uk CREATED:20230324T132907Z DESCRIPTION:Abstract: Intracellular transport is essential for neuronal f unction and survival. The most effective plus end-directed neuronal tran sporter is the kinesin-3 KIF1C\, which transports large secretory vesicl es and endosomes in both axons and dendrites. Cytoplasmic dynein is the major minus-end directed transporter. Thus both motors transport cargo w ith opposite polarity. KIF1C depletion reduces both microtubule plus and minus end-directed vesicle transport in cells\, suggesting that KIF1C f acilitates dynein-mediated transport by an unknown mechanism. Such a co- dependence of opposite polarity motors for bidirectional cargo transport has also been observed for kinesin-1 and dynein. However\, when both mo tors were linked together artificially in vitro\, they undertook a tug-o f-war with little net motility. Here we reconstituted complexes of dynei n and KIF1C in the presence of dynactin and cargo adapters from purified recombinant human proteins and show that both motors can bind simultane ously to cargo adapters Hook3\, BICD2 and BICDR1 to form co-motile compl exes. Quaternary complexes of dynein\, dynactin\, hook3 and KIF1C (DDHK) form most efficiently and show directional\, processive motility toward s the plus and the minus end of microtubules in single molecule assays. KIF1C increases the initiation\, duration and distance of minus end-dire cted runs\, both by acting as a processivity tether and because KIF1C fa cilitates the recruitment of a second dynein to dynactin and hook3. Base d on intensity measurements of motile complexes we propose a stoichiomet ry of two dynein dimers\, two KIF1C dimers\, two hook3 dimers and one dy nactin in DDHK complexes. Directional switching of DDHK complexes was re latively rare\, suggesting that the adapter-mediated coupling of opposit e polarity motors primarily supports processive unidirectional transport \, prevents tug-of-war and enables the super-processive KIF1C to extend dynein-driven runs. Mutations in KIF1C cause hereditary spastic parapleg ia and cerebellar dysfunction in human patients. Two pathogenic mutation s (P176L and R169W) maintain fast\, processive single molecule motility in vitro\, but with decreased run length and slightly increased unloaded velocity compared to the wildtype motor. Under load in an optical trap\ , force generation by these mutants is severely reduced. In cells\, the same mutants are impaired in producing sufficient force to efficiently r elocate organelles. Our results show how its mechanics supports KIF1C’s role as an intracellular transporter and explain how pathogenic mutation s at the microtubule-binding interface of KIF1C impair the cellular func tion of these long-distance transporters and result in neuronal disease. LOCATION:IBRB Lecture Theatre CATEGORIES:BiomedicalSciences,DivisionalSeminars LAST-MODIFIED:20230324T132907Z ORGANIZER;CN=Jas Bains: END:VEVENT END:VCALENDAR