How Dynein Moves Along Microtubules

Bhabha, Gira; Johnson, Graham; Schroeder, Courtney M.; Vale, Ronald D.

doi:10.1016/j.tibs.2015.11.004

Cited by 130 publications

(141 citation statements)

References 68 publications

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“…7 C and D). Bhabha et al (33) also postulated that repriming (reversal of the working stroke) in the detached stepping head biases the MTBD position in the forward minus-end direction. The attachment can occur at any of several of the tubulin subunits in its range.…”

Section: Discussionmentioning

confidence: 99%

“…EM studies with both cytoplasmic (30,31) and axonemal (32) dynein provide some support for stalk rotation. Rotations of the ring may enable dynein to reach various tubulin subunits during a step (33). In contrast, other structural studies of axonemal dynein report that the stalk and ring domain rotate much less relative to the MT throughout different nucleotide states (34,35).…”

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confidence: 93%

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Angular measurements of the dynein ring reveal a stepping mechanism dependent on a flexible stalk

Lippert

Dadosh

Hadden

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The force-generating mechanism of dynein differs from the forcegenerating mechanisms of other cytoskeletal motors. To examine the structural dynamics of dynein's stepping mechanism in real time, we used polarized total internal reflection fluorescence microscopy with nanometer accuracy localization to track the orientation and position of single motors. By measuring the polarized emission of individual quantum nanorods coupled to the dynein ring, we determined the angular position of the ring and found that it rotates relative to the microtubule (MT) while walking. Surprisingly, the observed rotations were small, averaging only 8.3°, and were only weakly correlated with steps. Measurements at two independent labeling positions on opposite sides of the ring showed similar small rotations. Our results are inconsistent with a classic power-stroke mechanism, and instead support a flexible stalk model in which interhead strain rotates the rings through bending and hinging of the stalk. Mechanical compliances of the stalk and hinge determined based on a 3.3-μs molecular dynamics simulation account for the degree of ring rotation observed experimentally. Together, these observations demonstrate that the stepping mechanism of dynein is fundamentally different from the stepping mechanisms of other well-studied MT motors, because it is characterized by constant small-scale fluctuations of a large but flexible structure fully consistent with the variable stepping pattern observed as dynein moves along the MT.ynein is a molecular motor that walks processively toward the minus end of microtubules (MTs) in an ATP-dependent manner (1-3). Axonemal dyneins drive the motility of eukaryotic cilia and flagella, whereas cytoplasmic dynein is responsible for a wide range of functions within eukaryotic cells, including the retrograde transport of cargo such as autophagosomes in neurons (4), alignment of the mitotic spindle (5, 6), and chromosome segregation during mitosis (7). Disruption of dynein-mediated neuronal transport has been implicated in neurodegeneration (8), and mutations in dynein and dynein-associated proteins can cause a range of diseases, including spinal muscular atrophy (9, 10), lissencephaly (11) and Charcot-Marie-Tooth disease type 2 (reviewed in ref. 12). Despite the importance of dynein function, the mechanism by which dynein walks along the MT is not yet well understood.The motor domains of dynein are formed from six concatenated AAA domains, interrupted by a long, antiparallel, coiled-coil stalk that emerges from AAA4 and terminates in the microtubulebinding domain (MTBD) and the buttress that extends from AAA5 and is thought to stabilize the stalk (13,14). Two motor domains form a dimer via their N-terminal tails (2, 3). ATP binding and hydrolysis drive dynein mechanochemistry; the binding of ATP to AAA1 induces a conformational change leading to dissociation of the MTBD from the MT. Hydrolysis on the dissociated head induces a primed conformation that then rebinds to the MT. The forward step, or power stroke,...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 93%

Angular measurements of the dynein ring reveal a stepping mechanism dependent on a flexible stalk

Lippert

Dadosh

Hadden

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…It functions as an ~1.2 MDa multi-protein complex with two heavy chains, each of which contains a motor domain at the C-terminus and a “tail” domain that mediates interactions with accessory factors at its N-terminus [247,248,249]. Cytoplasmic dynein is the major microtubule minus-end-directed motor protein that transports a wide range of cargoes (e.g., organelles, proteins, and mRNA) in eukaryotic cells.…”

Section: Sliding and Sorting Microtubulesmentioning

confidence: 99%

“…Cytoplasmic dynein is the major microtubule minus-end-directed motor protein that transports a wide range of cargoes (e.g., organelles, proteins, and mRNA) in eukaryotic cells. There have been several advances in our understanding of cytoplasmic dynein’s structure, biochemistry, and motility [247,248,249]. Here I highlight dynein’s function in spindle organization, focusing on its microtubule sliding and sorting functions.…”

Section: Sliding and Sorting Microtubulesmentioning

confidence: 99%

Metaphase Spindle Assembly

Kapoor

2017

Biology

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“…for DNA/RNA replications, transcriptions, and translations), and are at the heart of many other specific biological processes, which make them critical for regulatory systems and communication between cells. As structural scaffolding, proteins also form rigid but flexible supports for different functions, such as in the cytoskeleton of eukaryotic cells [2], or in motor proteins in muscle cells [3,4]. …”

Section: Automated Protein Design: Radical Protein Engineering By mentioning

confidence: 99%

Recent advances in automated protein design and its future challenges

Setiawan

Brender

Zhang

2018

Expert Opinion on Drug Discovery

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Introduction Protein function is determined by protein structure which is in turn determined by the corresponding protein sequence. If the rules that cause a protein to adopt a particular structure are understood, it should be possible to refine or even redefine the function of a protein by working backwards from the desired structure to the sequence. Automated protein design attempts to calculate the effects of mutations computationally with the goal of more radical or complex transformations than are accessible by experimental techniques. Areas covered The authors give a brief overview of the recent methodological advances in computer-aided protein design, showing how methodological choices affect final design and how automated protein design can be used to address problems considered beyond traditional protein engineering, including the creation of novel protein scaffolds for drug development. Also, the authors address specifically the future challenges in the development of automated protein design. Expert opinion Automated protein design holds potential as a protein engineering technique, particularly in cases where screening by combinatorial mutagenesis is problematic. Considering solubility and immunogenicity issues, automated protein design is initially more likely to make an impact as a research tool for exploring basic biology in drug discovery than in the design of protein biologics.

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How Dynein Moves Along Microtubules

Cited by 130 publications

References 68 publications

Angular measurements of the dynein ring reveal a stepping mechanism dependent on a flexible stalk

Angular measurements of the dynein ring reveal a stepping mechanism dependent on a flexible stalk

Metaphase Spindle Assembly

Recent advances in automated protein design and its future challenges

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