AAA+ Ring and Linker Swing Mechanism in the Dynein Motor

Roberts, A. J.; Numata, Naoki; Walker, Matthew; Kato, Yusuke; Malkova, Bara; Kon, Takahide; Ohkura, Reiko; Arisaka, Fumio; Knight, Peter J.; Sutoh, Kazuo; Burgess, Simon

doi:10.1016/j.cell.2008.11.049

Cited by 205 publications

(269 citation statements)

References 47 publications

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“…The inactivation by the accumulated stress renders the switching shear dependent, in a way that is somewhat In the original version of the excitable-dynein hypothesis, dynein does not necessarily detach from the adjacent microtubule. (B)The current conception of the dynein power stroke and recovery (Burgess et al, 2003, Roberts et al, 2009. The various models of flagellar beating that are based on the kinetics of the dynein cross-bridge cycle incorporate considerable variation in the details of coupling between the bridge cycle and the beat, including metachronal (sequential) activation, multiple cycle activation and cooperative group activation with stress-based termination.…”

Section: Dynein Cross-bridge Cyclementioning

confidence: 99%

Flagellar and ciliary beating: the proven and the possible

Lindemann

Lesich

2010

Journal of Cell Science

258

215

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SummaryThe working mechanism of the eukaryotic flagellar axoneme remains one of nature's most enduring puzzles. The basic mechanical operation of the axoneme is now a story that is fairly complete; however, the mechanism for coordinating the action of the dynein motor proteins to produce beating is still controversial. Although a full grasp of the dynein switching mechanism remains elusive, recent experimental reports provide new insights that might finally disclose the secrets of the beating mechanism: the special role of the inner dynein arms, especially dynein I1 and the dynein regulatory complex, the importance of the dynein microtubule-binding affinity at the stalk, and the role of bending in the selection of the active dynein group have all been implicated by major new evidence. This Commentary considers this new evidence in the context of various hypotheses of how axonemal dynein coordination might work.

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Section: Dynein Cross-bridge Cyclementioning

confidence: 99%

Flagellar and ciliary beating: the proven and the possible

Lindemann

Lesich

2010

Journal of Cell Science

258

215

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“…1). The ATPcatalytic site largely responsible for coupling force production with substrate affinity is located on the side of the ring opposite the site where the stalk emerges (8,9). These two functionally coordinated domains are separated by a distance up to 20 -25 nm.…”

mentioning

confidence: 99%

A Low Affinity Ground State Conformation for the Dynein Microtubule Binding Domain

McNaughton

Tikhonenko

Banavali

et al. 2010

Journal of Biological Chemistry

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Dynein interacts with microtubules through a dedicated binding domain that is dynamically controlled to achieve high or low affinity, depending on the state of nucleotide bound in a distant catalytic pocket. The active sites for microtubule binding and ATP hydrolysis communicate via conformational changes transduced through a ϳ10-nm length antiparallel coiled-coil stalk, which connects the binding domain to the roughly 300-kDa motor core. Recently, an x-ray structure of the murine cytoplasmic dynein microtubule binding domain (MTBD) in a weak affinity conformation was published, containing a covalently constrained ␤ ؉ registry for the coiled-coil stalk segment (Carter, A. P., Garbarino, J. E., Wilson-Kubalek, E. M., Shipley, W. E., Cho, C., Milligan, R. A., Vale, R. D., and Gibbons, I. R. (2008) Science 322, 1691-1695). We here present an NMR analysis of the isolated MTBD from Dictyostelium discoideum that demonstrates the coiled-coil ␤ ؉ registry corresponds to the low energy conformation for this functional region of dynein. Addition of sequence encoding roughly half of the coiled-coil stalk proximal to the binding tip results in a decreased affinity of the MTBD for microtubules. In contrast, addition of the complete coiled-coil sequence drives the MTBD to the conformationally unstable, high affinity binding state. These results suggest a thermodynamic coupling between conformational free energy differences in the ␣ and ␤ ؉ registries of the coiled-coil stalk that acts as a switch between high and low affinity conformations of the MTBD. A balancing of opposing conformations in the stalk and MTBD enables potentially modest long-range interactions arising from ATP binding in the motor core to induce a relaxation of the MTBD into the stable low affinity state.Dyneins comprise one of the three families of cytoskeletonbased molecular motors that generate force and translocate cargo in eukaryotic cells (2). These motors work by coupling high and low affinity binding to microtubule or actin filaments, with force producing conformational changes driven by an ATP catalytic cycle (3-5). The coordination between these steps is critical for efficient linear movement. Force production occurs after tight binding is achieved, in a manner that both moves cargo forward and facilitates motor repositioning to advance another step. Although ATP hydrolysis and product release provide the thermodynamic driving force for motility, binding to the microtubule or actin filaments also provides feedback to the catalytic pocket and influences the catalytic rate.An understanding of how substrate affinity is achieved and how it is coupled to nucleotide hydrolysis remains an important problem for all three families of motors (dynein, kinesin, and myosin). For dynein, these issues are particularly complex. In contrast to the close proximity of the substrate-binding domains and catalytic sites in kinesin or myosin-type motors (5), the ATP-sensitive interaction of dynein with microtubules occurs through contacts within a relatively small (ϳ125 ...

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“…The transport process involves the action of motor proteins which attach to the vesicles or endosomes and move along microtubules. products of ATP hydrolysis; adenosine diphosphate (ADP) + Pi are released the MTBD once again forms a strong association with microtubules and the linker moves back to its original position thus producing the power stroke of dynein [26,28,38,41,44]. The motor domains of dynein coordinate so that it appears to "walk" along the microtubule.…”

Section: Introductionmentioning

confidence: 99%

From the Cell Membrane to the Nucleus: Unearthing Transport Mechanisms for Dynein

et al. 2012

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Mutations in the motor protein cytoplasmic dynein have been found to cause Charcot-MarieTooth disease in humans, spinal muscular atrophy and severe intellectual disabilities in humans.In mouse models neurodegeneration is observed. We sought to develop a novel model which could incorporate the effect of mutations on distance travelled and velocity. A mechanical model for the dynein mediated transport of endosomes is derived from first principles and solved numerically. The effects of variations in model parameter values are analysed to find those that have a significant impact on velocity and distance travelled. The model successfully describes the processivity of dynein and matches qualitatively the velocity profiles observed in experiments.

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AAA+ Ring and Linker Swing Mechanism in the Dynein Motor

Cited by 205 publications

References 47 publications

Flagellar and ciliary beating: the proven and the possible

Flagellar and ciliary beating: the proven and the possible

A Low Affinity Ground State Conformation for the Dynein Microtubule Binding Domain

From the Cell Membrane to the Nucleus: Unearthing Transport Mechanisms for Dynein

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