Regulators of the cytoplasmic dynein motor

Kardon, Julia R.; Vale, Ronald D.

doi:10.1038/nrm2804

Cited by 559 publications

(600 citation statements)

References 164 publications

(203 reference statements)

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“…The attachment to the wide variety of different cargos is probably assured by different multifunctional adaptors such as dynactin which regulate dynein function [187]. The structure of cytoplasmic dynein is more complicated than those of kinesins -a fact which is also reflected in its very high molecular weight of 1.2 MDa [256].…”

Section: Dyneinmentioning

confidence: 99%

Intracellular transport driven by cytoskeletal motors: General mechanisms and defects

2015

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Cells are the elementary units of living organisms, which are able to carry out many vital functions. These functions rely on active processes on a microscopic scale. Therefore, they are strongly out-of-equilibrium systems, which are driven by continuous energy supply. The tasks that have to be performed in order to maintain the cell alive require transportation of various ingredients, some being small, others being large. Intracellular transport processes are able to induce concentration gradients and to carry objects to specific targets. These processes cannot be carried out only by diffusion, as cells may be crowded, and quite elongated on molecular scales. Therefore active transport has to be organized.The cytoskeleton, which is composed of three types of filaments (microtubules, actin and intermediate filaments), determines the shape of the cell, and plays a role in cell motion. It also serves as a road network for a special kind of vehicles, namely the cytoskeletal motors. These molecules can attach to a cytoskeletal filament, perform directed motion, possibly carrying along some cargo, and then detach.It is a central issue to understand how intracellular transport driven by molecular motors is regulated. The interest for this type of question was enhanced when it was discovered that intracellular transport breakdown is one of the signatures of some neuronal diseases like the Alzheimer.We give a survey of the current knowledge on microtubule based intracellular transport. Our review includes on the one hand an overview of biological facts, obtained from experiments, and on the other hand a presentation of some modeling attempts based on cellular automata. We present some background knowledge on the original and variants of the TASEP (Totally Asymmetric Simple Exclusion Process), before turning to more application oriented models. After addressing microtubule based transport in general, with a focus on in vitro experiments, and on cooperative effects in the transportation of large cargos by multiple motors, we concentrate on axonal transport, because of its relevance for neuronal diseases. Some important characteristics of axonal transport is that it takes place in a confined environment; Besides several types of motors are involved, that move in opposite directions. It is a challenge to understand how this bidirectional transport is organized. We review several features that could contribute to the efficiency of bidirectional transport in the axon, including in particular the role of motor-motor interactions and of the dynamics of the underlying microtubule network. Finally, we also discuss some open questions that may be relevant for future research in this field.

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Section: Dyneinmentioning

confidence: 99%

Intracellular transport driven by cytoskeletal motors: General mechanisms and defects

2015

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“…There are several such adapter proteins that link dynein/dynactin to different cargoes like organelles and kinetochores or to the cell cortex (Kardon & Vale, 2009; McKenney et al , 2014). One example is the metazoan‐specific adapter protein Bicaudal‐D2 (BicD2) that is critical for bidirectional transport of mRNA particles and contributes to the positioning of the endoplasmic reticulum, the Golgi apparatus and the nucleus (Bullock & Ish‐Horowicz, 2001; Hoogenraad et al , 2001; Hoogenraad & Akhmanova, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…However, Lis1 was not required for dynein end tracking in a minimal in vitro reconstitution (Duellberg et al , 2014), raising the question as to why Lis1 is needed for dynein end tracking in cells. Lis1 is a homodimeric 45 kDa protein that binds directly to the dynein motor domain (Mateja et al , 2006; Kardon & Vale, 2009), and was reported to induce a more strongly microtubule‐bound state of dynein (Yamada et al , 2008; McKenney et al , 2010; Torisawa et al , 2011), thereby increasing the force produced by dynein (McKenney et al , 2010; Reddy et al , 2016), and slowing down microtubule transport by surface‐immobilised dynein motors (Yamada et al , 2008; Torisawa et al , 2011; Wang et al , 2013). …”

Section: Introductionmentioning

confidence: 99%

Combinatorial regulation of the balance between dynein microtubule end accumulation and initiation of directed motility

et al. 2017

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Cytoplasmic dynein is involved in a multitude of essential cellular functions. Dynein's activity is controlled by the combinatorial action of several regulatory proteins. The molecular mechanism of this regulation is still poorly understood. Using purified proteins, we reconstitute the regulation of the human dynein complex by three prominent regulators on dynamic microtubules in the presence of end binding proteins (EBs). We find that dynein can be in biochemically and functionally distinct pools: either tracking dynamic microtubule plus‐ends in an EB‐dependent manner or moving processively towards minus ends in an adaptor protein‐dependent manner. Whereas both dynein pools share the dynactin complex, they have opposite preferences for binding other regulators, either the adaptor protein Bicaudal‐D2 (BicD2) or the multifunctional regulator Lissencephaly‐1 (Lis1). BicD2 and Lis1 together control the overall efficiency of motility initiation. Remarkably, dynactin can bias motility initiation locally from microtubule plus ends by autonomous plus‐end recognition. This bias is further enhanced by EBs and Lis1. Our study provides insight into the mechanism of dynein regulation by dissecting the distinct functional contributions of the individual members of a dynein regulatory network.

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“…9 Lis1, NudE and NudEL are important for Dynein function at kinetochores, nuclear and spindle positioning, as well as organelle and mRNA transport. 8 Bicaudal D also plays a role in Dynein-mediated organelle transport and, together with NudE and NudEL, targets Dynein to the nuclear envelope where it contributes to the separation of spindle poles in early mitosis. 10 The Rod, ZW10 and Zwilch (RZZ) complex and Spindly target Keywords: Aurora A, Dynein, error correction, kinetochore, spindle pole Dynein specifically to kinetochores, coupling its function to kinetochore-microtubule attachments and the spindle assembly checkpoint.…”

Section: Introductionmentioning

confidence: 99%

“…7 Dynein interacts with many different proteins that regulate its activity and localization, enabling Dynein to perform its various cellular tasks. 8 Dynactin, another large multi-protein complex (1 MDa) is involved in most Dynein functions, both by targeting it to specific locations and by increasing its processivity. 9 Lis1, NudE and NudEL are important for Dynein function at kinetochores, nuclear and spindle positioning, as well as organelle and mRNA transport.…”

Section: Introductionmentioning

confidence: 99%