A structural change in the kinesin motor protein that drives motility

Rice, Sarah E.; Lin, Abel W.; Safer, Daniel; Hart, Cynthia L.; Naber, Nariman; Carragher, Bridget; Cain, Shane M.; Pechatnikova, Elena; Wilson-Kubalek, Elizabeth M.; Whittaker, Michael; Pate, Edward; Cooke, Roger; Taylor, E. W.; Milligan, Ronald A.; Vale, Ronald D.

doi:10.1038/45483

Cited by 743 publications

(913 citation statements)

References 47 publications

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“…That the Brownian search-and-catch significantly contributes to force generation in myosin-V challenges the theory that biological molecular motors, such as myosin, kinesin and dynein, generate force primarily from a structural change 14,15,40,41 (in the case of myosin-V, this is the lever-arm swing). More likely, the work distribution between the structural change and the Brownian searchand-catch would vary with the molecular motor.…”

Section: Discussionmentioning

confidence: 99%

Switching of myosin-V motion between the lever-arm swing and Brownian search-and-catch

et al. 2012

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motor proteins are force-generating nanomachines that are highly adaptable to their everchanging biological environments and have a high energy conversion efficiency. Here we constructed an imaging system that uses optical tweezers and a DnA handle to visualize elementary mechanical processes of a nanomachine under load. We apply our system to myosin-V, a well-known motor protein that takes 72 nm 'hand-over-hand' steps composed of a 'lever-arm swing' and a 'Brownian search-and-catch'. We find that the lever-arm swing generates a large proportion of the force at low load ( < 0.5 pn), resulting in 3 k B T of work. At high load (1.9 pn), however, the contribution of the Brownian search-and-catch increases to dominate, reaching 13 k B T of work. We believe the ability to switch between these two forcegeneration modes facilitates myosin-V function at high efficiency while operating in a dynamic intracellular environment.1 Soft Biosystem Group, Laboratories for Nanobiology, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan. 2 Graduate School of Medicine, Osaka University, 1-3 Yamadaoka, Suita, 565-0871, Japan. switching of myosin-V motion between the lever-arm swing and Brownian search-and-catch

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Section: Discussionmentioning

confidence: 99%

Switching of myosin-V motion between the lever-arm swing and Brownian search-and-catch

et al. 2012

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“…This rapid release is biphasic: the first ADP is released at >200 s −1 , while the release of the second ADP is nucleotide-dependent, with ATP-stimulated release at >100 s −1 (Table 1, [16][17][18][19]). When interpreted in the context of the Rice et al neck linker model [20][21][22], these data lead to the following pathway (Figure 2, steps K1-K4). The first motor head collides with the microtubule and releases its ADP.…”

Section: A Consensus Mechanochemical Cycle For Dimeric Kinesinmentioning

confidence: 97%

To step or not to step? How biochemistry and mechanics influence processivity in Kinesin and Eg5

Valentine

Gilbert

2007

Current Opinion in Cell Biology

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Conventional kinesin and Eg5 are essential nanoscale motor proteins. Single-molecule and presteady-state kinetic experiments indicate that both motors use similar strategies to generate movement along microtubules, despite having distinctly different in vivo functions. Single molecules of kinesin, a long-distance cargo transporter, are highly processive, binding the microtubule and taking 100 or more sequential steps at velocities of up to 700 nm/s before dissociating, whereas Eg5, a motor active in mitotic spindle assembly, is also processive, but takes fewer steps at a slower rate. By dissecting the structural, biochemical and mechanical features of these proteins, we hope to learn how kinesin and Eg5 are optimized for their specific biological tasks, while gaining insight into how biochemical energy is converted into mechanical work.

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“…The R350 amino acid in particular is located at the end of the motor domain in close vicinity to the neck linker (aa 352-364) that has an important role in directionality and has mechanochemical implications for the motility of the protein. [7][8][9] There is evidence that the KIF1A protein functions as the primary motor for synaptic-and dense-core vesicle transport. 10,11 In animal models of C. elegans with mutations in the KIF1A ortholog (unc-104), a decreased transport capacity of synaptic vesicle precursors in the axons has been evidenced.…”

Section: Rearrangement Detectionmentioning

confidence: 99%

KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations

et al. 2012

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The hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases characterised by progressive spasticity in the lower limbs. The nosology of autosomal recessive forms is complex as most mapped loci have been identified in only one or a few families and account for only a small percentage of patients. We used next-generation sequencing focused on the SPG30 chromosomal region on chromosome 2q37.3 in two patients from the original linked family. In addition, wide genome scan and candidate gene analysis were performed in a second family of Palestinian origin. We identified a single homozygous mutation, p.R350G, that was found to cosegregate with the disease in the SPG30 kindred and was absent in 970 control chromosomes while affecting a strongly conserved amino acid at the end of the motor domain of KIF1A. Homozygosity and linkage mapping followed by mutation screening of KIF1A allowed us to identify a second mutation, p.A255V, in the second family. Comparison of the clinical features with the nature of the mutations of all reported KIF1A families, including those reported recently with hereditary sensory and autonomic neuropathy, suggests phenotypegenotype correlations that may help to understand the mechanisms involved in motor neuron degeneration. We have shown that mutations in the KIF1A gene are responsible for SPG30 in two autosomal recessive HSP families. In published families, the nature of the KIF1A mutations seems to be of good predictor of the underlying phenotype and vice versa. INTRODUCTIONThe hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases characterised by progressive spasticity in the lower limbs. 1 The mode of inheritance may be autosomal dominant, autosomal recessive (ARHSP) or X-linked. More than 48 different loci (SPGn) have been mapped so far, and 23 responsible genes identified. The corresponding proteins are often involved in intracellular trafficking or mitochondrial functions. 2,3 Clinically, one can distinguish between pure and complicated forms of HSP. 1,2 Pure forms consist of isolated pyramidal signs, such as spasticity, abnormal reflexes (brisk reflexes and Babinski sign) and motor deficit, often associated with sphincter disturbances and deep sensory loss. In the complicated forms of HSP the disease is variably associated with numerous combinations of neurological and extraneurological signs, such as cerebellar ataxia, dysarthria, mental retardation, peripheral neuropathy, optic atrophy, retinitis pigmentosa and/or hearing loss, which may be accompanied by abnormal brain MRI (atrophy of the cortex, cerebellum or corpus callosum, white matter abnormalities, etc).Mutations in the KIF1A gene (MIM 601255) were very recently described in two different clinically and genetically heterogeneous groups of neurodegenerative diseases. 4,5 In hereditary sensory and autonomic neuropathy (HSAN), all patients from four families with different origins shared a common hom...

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A structural change in the kinesin motor protein that drives motility

Cited by 743 publications

References 47 publications

Switching of myosin-V motion between the lever-arm swing and Brownian search-and-catch

Switching of myosin-V motion between the lever-arm swing and Brownian search-and-catch

To step or not to step? How biochemistry and mechanics influence processivity in Kinesin and Eg5

KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations

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