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Abstract
Kinesin-1 is a two-headed motor that takes processive 8-nm hand-over-hand steps and transports intracellular cargos toward the plus-end of microtubules. Processive motility requires a gating mechanism to coordinate the mechanochemical cycles of the two heads. Kinesin gating involves neck linker (NL), a short peptide that interconnects the heads, but it remains unclear whether gating is facilitated by the NL orientation or tension. Using optical trapping, we measured the force-dependent microtubule release rate of kinesin monomers under different nucleotide conditions and pulling geometries. We find that pulling NL in the backward direction inhibits nucleotide binding and subsequent release from the microtubule. This inhibition is independent of the magnitude of tension (2-8 pN) exerted on NL. Our results provide evidence that the front head of a kinesin dimer is gated by the backward orientation of its NL until the rear head releases from the microtubule.
Highlights
Kinesin-1 is a dimeric motor that carries membranous organelles and vesicles towards the synapse in neurons (Hirokawa et al, 2009)
This coordinated movement is facilitated by a gating mechanism that keeps the heads out of phase such that chemical or structural transitions in one head are inhibited until the partner head proceeds through its mechanochemical cycle
In the rear-head gating model (Crevel et al, 2004; Schief et al, 2004), ATP hydrolysis or MT release in the rear head are accelerated relative to the front head. Both models are consistent with the stepping of the rear head as the front head remains bound to a MT during processive motility, and they are not mutually exclusive
Summary
Kinesin-1 ( referred to as kinesin) is a dimeric motor that carries membranous organelles and vesicles towards the synapse in neurons (Hirokawa et al, 2009). The heads alternately take a step (a pattern termed hand-over-hand stepping), in which the front head remains bound to the MT as the rear head steps forward (Asbury et al, 2003; Kaseda et al, 2003; Yildiz et al, 2004) This coordinated movement is facilitated by a gating mechanism that keeps the heads out of phase such that chemical or structural transitions in one head are inhibited until the partner head proceeds through its mechanochemical cycle. In the rear-head gating model (Crevel et al, 2004; Schief et al, 2004), ATP hydrolysis or MT release in the rear head are accelerated relative to the front head Both models are consistent with the stepping of the rear head as the front head remains bound to a MT during processive motility, and they are not mutually exclusive
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