Recruitment of two dyneins to an mRNA-dependent Bicaudal D transport complex

Sladewski, Thomas E.; Billington, Neil; Ali, M. Yusuf; Bookwalter, Carol S.; Lu, Hailong; Krementsova, Elena B.; Schroer, Trina A.; Trybus, Kathleen M.

doi:10.7554/elife.36306

Cited by 64 publications

(92 citation statements)

References 50 publications

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“…2C). As expected given recent findings (McClintock et al, 2018;Sladewski et al, 2018), loss of RNA binding significantly compromised the Egl-BicD interaction (Fig. 2C).…”

Section: Resultssupporting

confidence: 91%

“…We therefore hypothesized that Dlc is required for Egl dimerization, and that dimerization is a pre-requisite for efficient RNA binding. In addition, although Egl and BicD can directly interact, the Bullock and Trybus labs recently demonstrated that this interaction is greatly enhanced by RNA (McClintock et al, 2018;Sladewski et al, 2018). Thus, we further posit that by affecting the ability of Egl to bind RNA, loss of dimerization also affects its ability to interact with BicD.…”

Section: Resultsmentioning

confidence: 66%

“…Thus, in theory, both of the Egl binding partners are capable of linking mRNA-bound Egl with the Dynein motor. Recent in vitro studies have shown that a minimal complex consisting of RNA, Egl, BicD, Dynactin and Dynein is sufficient for transport (McClintock et al, 2018;Sladewski et al, 2018). Whether or not this complex is sufficient for mRNA localization in vivo, however, is not known.…”

Section: Introductionmentioning

confidence: 99%

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The Egalitarian binding partners Dynein light chain and Bicaudal-D act sequentially to link mRNA to the Dynein motor

et al. 2019

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A conserved mechanism of polarity establishment is the localization of mRNA to specific cellular regions. Although it is clear that many mRNAs are transported along microtubules, much less is known about the mechanism by which these mRNAs are linked to microtubule motors. The RNA binding protein Egalitarian (Egl) is necessary for localization of several mRNAs in Drosophila oocytes and embryos. Egl also interacts with Dynein light chain (Dlc) and Bicaudal-D (BicD). The role of Dlc and BicD in mRNA localization has remained elusive. Both proteins are required for oocyte specification, as is Egl. Null alleles in these genes result in an oogenesis block. In this report, we used an shRNA-depletion strategy to overcome the oogenesis block. Our findings reveal that the primary function of Dlc is to promote Egl dimerization. Loss of dimerization compromises the ability of Egl to bind RNA. Consequently, Egl is not bound to cargo, and is not able to efficiently associate with BicD and the Dynein motor. Our results therefore identify the key molecular steps required for assembling a localization-competent mRNP.

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“…2C). As expected given recent findings (McClintock et al, 2018;Sladewski et al, 2018), loss of RNA binding significantly compromised the Egl-BicD interaction (Fig. 2C).…”

Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

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The Egalitarian binding partners Dynein light chain and Bicaudal-D act sequentially to link mRNA to the Dynein motor

et al. 2019

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“…BICD2 has also been implicated in nuclear positioning (Splinter et al, 2012;Hu et al, 2013). Furthermore, the C-terminal region of BICD proteins can bend back on itself to produce an autoinhibited state (Terawaki et al, 2015;Liu et al, 2013;Wharton and Struhl, 1989;Urnavicius et al, 2015), which can be relieved by cargo binding (Liu et al, 2013;Huynh and Vale, 2017;McClintock et al, 2018;Sladewski et al, 2018), suggesting an efficient mechanism to regulate dynein motility.…”

Section: Dynein Activatorsmentioning

confidence: 99%

Dynein activators and adaptors at a glance

Olenick

Holzbaur

2019

Journal of Cell Science

174

194

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Cytoplasmic dynein-1 (hereafter dynein) is an essential cellular motor that drives the movement of diverse cargos along the microtubule cytoskeleton, including organelles, vesicles and RNAs. A longstanding question is how a single form of dynein can be adapted to a wide range of cellular functions in both interphase and mitosis. Recent progress has provided new insightsdynein interacts with a group of activating adaptors that provide cargo-specific and/or function-specific regulation of the motor complex. Activating adaptors such as BICD2 and Hook1 enhance the stability of the complex that dynein forms with its required activator dynactin, leading to highly processive motility toward the microtubule minus end. Furthermore, activating adaptors mediate specific interactions of the motor complex with cargos such as Rab6-positive vesicles or ribonucleoprotein particles for BICD2, and signaling endosomes for Hook1. In this Cell Science at a Glance article and accompanying poster, we highlight the conserved structural features found in dynein activators, the effects of these activators on biophysical parameters, such as motor velocity and stall force, and the specific intracellular functions they mediate.

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“…Different cell types localise up to thousands of different mRNAs to specific domains which is required for a wide range of cellular functions [4][5][6][7] . New imaging techniques allowed to visualise individual-mRNA transport events in living neurons 8,9 , and reconstitutions revealed the first essential components of yeast and drosophila mRNA transport systems [10][11][12][13] . Still, as many building blocks of these reconstituted systems lack mammalian homologues, it remained unknown how any mammalian mRNA is loaded onto motor proteins, how copy number of transported mRNAs is controlled and what molecular mechanisms generate specificity to transport only certain mRNAs.…”

Section: Introductionmentioning

confidence: 99%

A reconstituted mammalian APC-kinesin complex selectively transports defined packages of mRNAs

Baumann

Komissarov

Gili

et al. 2019

Preprint

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Through the asymmetric distribution of mRNAs cells spatially regulate gene expression to create cytoplasmic domains with specialized functions. In mammalian neurons, mRNA localization is required for essential processes as cell polarization, migration and synaptic plasticity underlying long-term memory formation. The essential components driving cytoplasmic mRNA transport in neurons and mammalian cells are not known. Here, we report the first reconstitution of a mammalian mRNA transport system revealing that the tumour suppressor adenomatous polyposis coli (APC) forms stable complexes with the axonally localised -actin and 2B-tubulin mRNAs which are linked to a heterotrimeric kinesin-2 via the cargo adaptor KAP3. APC activates kinesin-2 and both proteins are sufficient to drive specific transport of defined mRNA packages. Guanine-rich sequences located in 3'UTRs of axonal mRNAs increase transport efficiency and balance the access of different mRNAs to the transport system. Our findings reveal for the first time a minimal set of proteins capable of driving kinesin-based, mammalian mRNA transport.Microtubule binding proteins as APC often function as catalysators for microtubule recruitment and processive movement of kinesins 28,29 . APC, harbouring an N-terminally localised KAP3 binding site 14 Fig.

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Recruitment of two dyneins to an mRNA-dependent Bicaudal D transport complex

Cited by 64 publications

References 50 publications

The Egalitarian binding partners Dynein light chain and Bicaudal-D act sequentially to link mRNA to the Dynein motor

The Egalitarian binding partners Dynein light chain and Bicaudal-D act sequentially to link mRNA to the Dynein motor

Dynein activators and adaptors at a glance

A reconstituted mammalian APC-kinesin complex selectively transports defined packages of mRNAs

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