Dynactin's pointed-end complex is a cargo-targeting module

Yeh, Ting‐Yu; Quintyne, Nicholas J.; Scipioni, Brett R.; Eckley, D. Mark; Schroer, Trina A.

doi:10.1091/mbc.e12-07-0496

Cited by 73 publications

(111 citation statements)

References 65 publications

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“…Alternatively, several studies have reported specialized roles for individual dynactin subunits in tailoring specific cargo transport and could be potential interaction sites for the N-terminal region of Hook proteins. The pointed end of dynactin p25/p27 has been shown to be vital for proper endosomal transport by dynein (2,13,14). Because fungal Hook proteins have been linked to endosomal transport, it is possible that the N terminus of Hook proteins interacts with p25/p27, but this would require for the coiled coil of Hook proteins to be oriented in a manner opposite to that of BICD2 along the dynactin filament.…”

Section: Discussionmentioning

confidence: 99%

“…The first major regulator to be identified was dynactin, a large multisubunit protein complex required for most functions of dynein within the cell. Dynactin forms a co-complex with dynein (5-8) that enhances the initial recruitment of dynein to the microtubule (9,10) and mediates the association of dynein with some intracellular cargos (11)(12)(13)(14). A second major dynein regulator, Lis1, binds to the dynein motor domain and blocks the required linker swing in the mechanochemical cycle for dynein; thus, Lis1 binding induces a non-motile state of dynein that binds tightly to the microtubule (15).…”

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confidence: 99%

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Hook Adaptors Induce Unidirectional Processive Motility by Enhancing the Dynein-Dynactin Interaction

Olenick

Tokito²,

Boczkowska³

et al. 2016

Journal of Biological Chemistry

106

146

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Cytoplasmic dynein drives the majority of minus end-directed vesicular and organelle motility in the cell. However, it remains unclear how dynein is spatially and temporally regulated given the variety of cargo that must be properly localized to maintain cellular function. Recent work has suggested that adaptor proteins provide a mechanism for cargo-specific regulation of motors. Of particular interest, studies in fungal systems have implicated Hook proteins in the regulation of microtubule motors. Here we investigate the role of mammalian Hook proteins, Hook1 and Hook3, as potential motor adaptors. We used optogenetic approaches to specifically recruit Hook proteins to organelles and observed rapid transport of peroxisomes to the perinuclear region of the cell. This rapid and efficient translocation of peroxisomes to microtubule minus ends indicates that mammalian Hook proteins activate dynein rather than kinesin motors. Biochemical studies indicate that Hook proteins interact with both dynein and dynactin, stabilizing the formation of a supramolecular complex. Complex formation requires the N-terminal domain of Hook proteins, which resembles the calponin-homology domain of end-binding (EB) proteins but cannot bind directly to microtubules. Single-molecule motility assays using total internal reflection fluorescence microscopy indicate that both Hook1 and Hook3 effectively activate cytoplasmic dynein, inducing longer run lengths and higher velocities than the previously characterized dynein activator bicaudal D2 (BICD2). Together, these results suggest that dynein adaptors can differentially regulate dynein to allow for organellespecific tuning of the motor for precise intracellular trafficking.Microtubules provide a polarized highway to facilitate the transport of organelles and vesicles throughout the cell. The minus ends of microtubules are usually nucleated near the cell center, with the plus ends oriented outward, toward the cell periphery. This polarity ensures that microtubule motors drive motility in a specific direction; kinesin motors generally drive plus end motility, whereas minus end traffic is primarily driven by cytoplasmic dynein. Regulation of these opposing motors is vital for cell survival, particularly in specialized cells like neurons that require efficient transport over long distances (1). However, it remains unclear how microtubule motors are spatially and temporally regulated to control the intracellular trafficking of specific cargo. As a single major form of cytoplasmic dynein drives the transport of a wide array of cargos, including endosomes, RNA granules, and mitochondria (2-4), it is likely that the transport properties of dynein are modulated by the binding of cargo-specific adaptor molecules.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Hook Adaptors Induce Unidirectional Processive Motility by Enhancing the Dynein-Dynactin Interaction

Olenick

Tokito²,

Boczkowska³

et al. 2016

Journal of Biological Chemistry

106

146

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“…Dynactin is a highly conserved multi-protein complex (Schroer, 2004) that is essential for normal neuronal function (LaMonte et al, 2002; Moughamian and Holzbaur, 2012). The base of dynactin is formed from a 37 nm-long actin-like polymer; both the Arp1 subunit that forms this polymer and additional dynactin subunits including p25 and p27 have been implicated in cargo binding (Holleran et al, 1996; Yeh et al, 2012; Zhang et al, 2011). Projecting from this base is a dimer of the subunit p150 Glued (Holzbaur et al, 1991).…”

Section: Molecular Motors Drive Transport Along the Neuronal Cytoskelmentioning

confidence: 99%

Axonal Transport: Cargo-Specific Mechanisms of Motility and Regulation

Maday

Twelvetrees

Moughamian

et al. 2014

Neuron

561

576

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Axonal transport is essential for neuronal function, and many neurodevelopmental and neurodegenerative diseases result from mutations in the axonal transport machinery. Anterograde transport supplies distal axons with newly synthesized proteins and lipids, including synaptic components required to maintain presynaptic activity. Retrograde transport is required to maintain homeostasis by removing aging proteins and organelles from the distal axon for degradation and recycling of components. Retrograde axonal transport also plays a major role in neurotrophic and injury response signaling. This review provides an overview of the axonal transport pathway and discusses its role in neuronal function.

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“…plex required for dynein-early endosome interaction (59,62). To confirm this idea, we used a biochemical pulldown assay to directly examine the physical interaction between the dynein HC labeled with GFP and the early endosome cargo labeled with mCherry-RabA.…”

Section: The Nudamentioning

confidence: 99%

Identification of a Novel Site in the Tail of Dynein Heavy Chain Important for Dynein Function in Vivo

Qiu

Zhang

Xiang

2013

Journal of Biological Chemistry

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Background:The dynein heavy chain tail is required for subunit interactions but not for in vitro motility. Results: A dynein tail mutation affects dynein function in vivo without affecting subunit interactions. Conclusion: A site upstream of the subunit interaction sites of the dynein tail is important in vivo. Significance: This study discovers a novel site of the dynein tail critical for motor function in vivo.

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Dynactin's pointed-end complex is a cargo-targeting module

Cited by 73 publications

References 65 publications

Hook Adaptors Induce Unidirectional Processive Motility by Enhancing the Dynein-Dynactin Interaction

Hook Adaptors Induce Unidirectional Processive Motility by Enhancing the Dynein-Dynactin Interaction

Axonal Transport: Cargo-Specific Mechanisms of Motility and Regulation

Identification of a Novel Site in the Tail of Dynein Heavy Chain Important for Dynein Function in Vivo

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