Key Points
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Cytoplasmic dynein is the only microtubule minus end-directed motor in the cytoplasm of most eukaryotic cells and therefore carries out a huge range of functions, including organelle and mRNA transport, nuclear and spindle positioning, and transport of the mitotic spindle assembly checkpoint proteins.
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The dynein motor functions as a holoenzyme, assembling into a complex with several smaller, non-catalytic subunits that help to connect it with dynein cargos as well as other regulatory factors that help to couple the dynein motor to its many cellular functions.
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Two dynein adaptors, dynactin and a complex of lissencephaly 1 (Lis1) and nuclear distribution protein E (NUDE) or NUDE-like (NUDEL) seem to be ubiquitously required for all dynein functions. Dynactin increases dynein processivity in vitro and helps to link dynein with its cargos and anchor points in the cell. LIS1–NUDE and LIS1–NUDEL might act primarily as a switch for dynein activity. Both dynactin and LIS1–NUDE and LIS1–NUDELmodulate dynein association with the plus ends of microtubules, which seems to be important for the delivery of dynein to its sites of activity.
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Bicaudal D and the Rod–ZW10–Zwilch (RZZ) complex are multifunctional dynein adaptors, but are restricted to metazoan organisms. Bicaudal D links dynein with several interphase cargos, and RZZ, with its partner Spindly, docks dynein at the mitotic kinetochore and might help to regulate the transition between the several dynein functions at the kinetochore.
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Small GTPases, which are highly specific to subcellular compartments, regulate dynein association with some of its cargos.
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Dynein's adaptors are heavily interconnected by physical interaction and by phenotype and so must cooperate to coordinate dynein function in the cell.
Abstract
Eukaryotic cells use cytoskeletal motor proteins to transport many different intracellular cargos. Numerous kinesins and myosins have evolved to cope with the various transport needs that have arisen during eukaryotic evolution. Surprisingly, a single cytoplasmic dynein (a minus end-directed microtubule motor) carries out similarly diverse transport activities as the many different types of kinesin. How is dynein coupled to its wide range of cargos and how is it spatially and temporally regulated? The answer could lie in the several multifunctional adaptors, including dynactin, lissencephaly 1, nuclear distribution protein E (NUDE) and NUDE-like, Bicaudal D, Rod–ZW10–Zwilch and Spindly, that regulate dynein function and localization.
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References
Karki, S. & Holzbaur, E. L. Cytoplasmic dynein and dynactin in cell division and intracellular transport. Curr. Opin. Cell Biol. 11, 45–53 (1999).
Vale, R. D. The molecular motor toolbox for intracellular transport. Cell 112, 467–480 (2003).
Neuwald, A. F., Aravind, L., Spouge, J. L. & Koonin, E. V. AAA+: a class of chaperone-like ATPases associated with the assembly, operation, and disassembly of protein complexes. Genome Res. 9, 27–43 (1999).
Vaughan, K. T. & Vallee, R. B. Cytoplasmic dynein binds dynactin through a direct interaction between the intermediate chains and p150Glued. J. Cell Biol. 131, 1507–1516 (1995).
Karki, S. & Holzbaur, E. L. Affinity chromatography demonstrates a direct binding between cytoplasmic dynein and the dynactin complex. J. Biol. Chem. 270, 28806–28811 (1995).
Tai, A. W., Chuang, J. Z., Bode, C., Wolfrum, U. & Sung, C. H. Rhodopsin's carboxy-terminal cytoplasmic tail acts as a membrane receptor for cytoplasmic dynein by binding to the dynein light chain Tctex-1. Cell 97, 877–887 (1999).
Purohit, A., Tynan, S. H., Vallee, R. & Doxsey, S. J. Direct interaction of pericentrin with cytoplasmic dynein light intermediate chain contributes to mitotic spindle organization. J. Cell Biol. 147, 481–492 (1999).
Farkasovsky, M. & Kuntzel, H. Cortical Num1p interacts with the dynein intermediate chain Pac11p and cytoplasmic microtubules in budding yeast. J. Cell Biol. 152, 251–262 (2001).
Ha, J. et al. A neuron-specific cytoplasmic dynein isoform preferentially transports TrkB signaling endosomes. J. Cell Biol. 181, 1027–1039 (2008).
Wang, Z., Khan, S. & Sheetz, M. P. Single cytoplasmic dynein molecule movements: characterization and comparison with kinesin. Biophys. J. 69, 2011–2023 (1995).
Mallik, R., Carter, B. C., Lex, S. A., King, S. J. & Gross, S. P. Cytoplasmic dynein functions as a gear in response to load. Nature 427, 649–652 (2004).
Reck-Peterson, S. L. et al. Single-molecule analysis of dynein processivity and stepping behavior. Cell 126, 335–348 (2006). Using recombinant dynein from S. cerevisiae , the authors directly observe the motion of single molecules of dynein for the first time, showing that it is a processive motor that requires dimerization for processivity. Their data strongly suggest that alternating steps of the dynein heads drive motility.
Gennerich, A. & Vale, R. D. Walking the walk: how kinesin and dynein coordinate their steps. Curr. Opin. Cell Biol. 21, 59–67 (2009).
Gennerich, A., Carter, A. P., Reck-Peterson, S. L. & Vale, R. D. Force-induced bidirectional stepping of cytoplasmic dynein. Cell 131, 952–965 (2007).
Nan, X., Sims, P. A. & Xie, X. S. Organelle tracking in a living cell with microsecond time resolution and nanometer spatial precision. Chemphyschem 9, 707–712 (2008).
Sims, P. A. & Xie, X. S. Probing dynein and kinesin stepping with mechanical manipulation in a living cell. Chemphyschem 13, 1511–1516 (2009).
Dixit, R., Ross, J. L., Goldman, Y. E. & Holzbaur, E. L. Differential regulation of dynein and kinesin motor proteins by tau. Science 319, 1086–1089 (2008).
Ross, J. L., Shuman, H., Holzbaur, E. L. & Goldman, Y. E. Kinesin and dynein-dynactin at intersecting microtubules: motor density affects dynein function. Biophys. J. 94, 3115–3125 (2008).
Toba, S., Watanabe, T. M., Yamaguchi-Okimoto, L., Toyoshima, Y. Y. & Higuchi, H. Overlapping hand-over-hand mechanism of single molecular motility of cytoplasmic dynein. Proc. Natl Acad. Sci. USA 103, 5741–5745 (2006).
Welte, M. A., Gross, S. P., Postner, M., Block, S. M. & Wieschaus, E. F. Developmental regulation of vesicle transport in Drosophila embryos: forces and kinetics. Cell 92, 547–557 (1998). The authors observe the motility and force generation of dynein- and kinesin-transported lipid droplets in living D. melanogaster embryos. Their data suggest that dynein and kinesin activities are coupled and that the protein Klarsicht might be involved in this coupling.
Laib, J. A., Marin, J. A., Bloodgood, R. A. & Guilford, W. H. The reciprocal coordination and mechanics of molecular motors in living cells. Proc. Natl Acad. Sci. USA 106, 3190–3195 (2009).
Ross, J. L., Ali, M. Y. & Warshaw, D. M. Cargo transport: molecular motors navigate a complex cytoskeleton. Curr. Opin. Cell Biol. 20, 41–47 (2008).
Gill, S. R. et al. Dynactin, a conserved, ubiquitously expressed component of an activator of vesicle motility mediated by cytoplasmic dynein. J. Cell Biol. 115, 1639–1650 (1991).
Schroer, T. A. & Sheetz, M. P. Two activators of microtubule-based vesicle transport. J. Cell Biol. 115, 1309–1318 (1991).
Schroer, T. A. Dynactin. Annu. Rev. Cell. Dev. Biol. 20, 759–779 (2004).
Adames, N. R. & Cooper, J. A. Microtubule interactions with the cell cortex causing nuclear movements in Saccharomyces cerevisiae. J. Cell Biol. 149, 863–874 (2000).
Lee, W. L., Kaiser, M. A. & Cooper, J. A. The offloading model for dynein function: differential function of motor subunits. J. Cell Biol. 168, 201–207 (2005).
Lee, W. L., Oberle, J. R. & Cooper, J. A. The role of the lissencephaly protein Pac1 during nuclear migration in budding yeast. J. Cell Biol. 160, 355–364 (2003).
Sheeman, B. et al. Determinants of S. cerevisiae dynein localization and activation: implications for the mechanism of spindle positioning. Curr. Biol. 13, 364–372 (2003).
Kardon, J. R., Reck-Peterson, S. L. & Vale, R. D. Regulation of the processivity and intracellular localization of Saccharomyces cerevisiae dynein by dynactin. Proc. Natl Acad. Sci. USA 106, 5669–5674 (2009).
Xiang, X., Beckwith, S. M. & Morris, N. R. Cytoplasmic dynein is involved in nuclear migration in Aspergillus nidulans. Proc. Natl Acad. Sci. USA 91, 2100–2104 (1994).
Xiang, X., Zuo, W., Efimov, V. P. & Morris, N. R. Isolation of a new set of Aspergillus nidulans mutants defective in nuclear migration. Curr. Genet. 35, 626–630 (1999).
Fischer, R. & Timberlake, W. E. Aspergillus nidulans apsA (anucleate primary sterigmata) encodes a coiled-coil protein required for nuclear positioning and completion of asexual development. J. Cell Biol. 128, 485–498 (1995).
Xiang, X., Han, G., Winkelmann, D. A., Zuo, W. & Morris, N. R. Dynamics of cytoplasmic dynein in living cells and the effect of a mutation in the dynactin complex actin-related protein Arp1. Curr. Biol. 10, 603–606 (2000).
Zhang, J., Li, S., Fischer, R. & Xiang, X. Accumulation of cytoplasmic dynein and dynactin at microtubule plus ends in Aspergillus nidulans is kinesin dependent. Mol. Biol. Cell 14, 1479–1488 (2003).
Hayashi, I., Wilde, A., Mal, T. K. & Ikura, M. Structural basis for the activation of microtubule assembly by the EB1 and p150Glued complex. Mol. Cell 19, 449–460 (2005).
Honnappa, S. et al. Key interaction modes of dynamic +TIP networks. Mol. Cell 23, 663–671 (2006).
Weisbrich, A. et al. Structure-function relationship of CAP-Gly domains. Nature Struct. Mol. Biol. 14, 959–967 (2007).
Hayashi, I., Plevin, M. J. & Ikura, M. CLIP170 autoinhibition mimics intermolecular interactions with p150Glued or EB1. Nature Struct. Mol. Biol. 14, 980–981 (2007). References 36–39 use structural and biochemical methods to define the interactions between CAP-Gly domains and both the zinc knuckle motif found in CLIP170 and the acidic C-terminal motif found in CLIP170, EB1 and α-tubulin. Competition and cooperation between these moderate affinity interactions are probably important to microtubule plus end tracking and its regulation.
Valetti, C. et al. Role of dynactin in endocytic traffic: effects of dynamitin overexpression and colocalization with CLIP-170. Mol. Biol. Cell 10, 4107–4120 (1999).
Lansbergen, G. et al. Conformational changes in CLIP-170 regulate its binding to microtubules and dynactin localization. J. Cell Biol. 166, 1003–1014 (2004).
Vaughan, P. S., Miura, P., Henderson, M., Byrne, B. & Vaughan, K. T. A role for regulated binding of p150Glued to microtubule plus ends in organelle transport. J. Cell Biol. 158, 305–319 (2002).
Watson, P., Forster, R., Palmer, K. J., Pepperkok, R. & Stephens, D. J. Coupling of ER exit to microtubules through direct interaction of COPII with dynactin. Nature Cell Biol. 7, 48–55 (2005).
Puls, I. et al. Mutant dynactin in motor neuron disease. Nature Genet. 33, 455–456 (2003).
Lai, C. et al. The G59S mutation in p150glued causes dysfunction of dynactin in mice. J. Neurosci. 27, 13982–13990 (2007).
Levy, J. R. et al. A motor neuron disease-associated mutation in p150Glued perturbs dynactin function and induces protein aggregation. J. Cell Biol. 172, 733–745 (2006).
Chevalier-Larsen, E. S., Wallace, K. E., Pennise, C. R. & Holzbaur, E. L. Lysosomal proliferation and distal degeneration in motor neurons expressing the G59S mutation in the p150Glued subunit of dynactin. Hum. Mol. Genet. 17, 1946–1955 (2008).
Tokito, M. K., Howland, D. S., Lee, V. M. & Holzbaur, E. L. Functionally distinct isoforms of dynactin are expressed in human neurons. Mol. Biol. Cell 7, 1167–1180 (1996).
Kim, H. et al. Microtubule binding by dynactin is required for microtubule organization but not cargo transport. J. Cell Biol. 176, 641–651 (2007).
Dixit, R., Levy, J. R., Tokito, M., Ligon, L. A. & Holzbaur, E. L. Regulation of dynactin through the differential expression of p150Glued isoforms. J. Biol. Chem. 283, 33611–33619 (2008).
Lomakin, A. J. et al. CLIP-170-dependent capture of membrane organelles by microtubules initiates minus-end directed transport. Dev. Cell 17, 323–333 (2009).
Holleran, E. A. et al. βIII spectrin binds to the Arp1 subunit of dynactin. J. Biol. Chem. 276, 36598–36605 (2001).
Muresan, V. et al. Dynactin-dependent, dynein-driven vesicle transport in the absence of membrane proteins: a role for spectrin and acidic phospholipids. Mol. Cell 7, 173–183 (2001).
De Matteis, M. A. & Morrow, J. S. Spectrin tethers and mesh in the biosynthetic pathway. J. Cell Sci. 113, 2331–2343 (2000).
Johansson, M. et al. Activation of endosomal dynein motors by stepwise assembly of Rab7-RILP-p150Glued, ORP1L, and the receptor βlll spectrin. J. Cell Biol. 176, 459–471 (2007).
Rocha, N. et al. Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7-RILP-p150Glued and late endosome positioning. J. Cell Biol. 185, 1209–1225 (2009). Through its conformational change in response to the cholesterol content of the membrane, ORPL1 regulates the association of dynein and dynactin with late endosomes and thus regulates their transport in response to cellular conditions.
Kumar, S., Zhou, Y. & Plamann, M. Dynactin-membrane interaction is regulated by the C-terminal domains of p150Glued. EMBO Rep. 2, 939–944 (2001).
Lee, I. H., Kumar, S. & Plamann, M. Null mutants of the neurospora actin-related protein 1 pointed-end complex show distinct phenotypes. Mol. Biol. Cell 12, 2195–2206 (2001).
Blangy, A., Arnaud, L. & Nigg, E. A. Phosphorylation by p34cdc2 protein kinase regulates binding of the kinesin-related motor HsEg5 to the dynactin subunit p150. J. Biol. Chem. 272, 19418–19424 (1997).
Deacon, S. W. et al. Dynactin is required for bidirectional organelle transport. J. Cell Biol. 160, 297–301 (2003).
Berezuk, M. A. & Schroer, T. A. Dynactin enhances the processivity of kinesin-2. Traffic 8, 124–129 (2007).
Waterman-Storer, C. M., Karki, S. & Holzbaur, E. L. The p150Glued component of the dynactin complex binds to both microtubules and the actin-related protein centractin (Arp-1). Proc. Natl Acad. Sci. USA 92, 1634–1638 (1995).
King, S. J. & Schroer, T. A. Dynactin increases the processivity of the cytoplasmic dynein motor. Nature Cell Biol. 2, 20–24 (2000).
Culver-Hanlon, T. L., Lex, S. A., Stephens, A. D., Quintyne, N. J. & King, S. J. A microtubule-binding domain in dynactin increases dynein processivity by skating along microtubules. Nature Cell Biol. 8, 264–270 (2006).
Moore, J. K., Sept, D. & Cooper, J. A. Neurodegeneration mutations in dynactin impair dynein-dependent nuclear migration. Proc. Natl Acad. Sci. USA 106, 5147–5152 (2009).
Dobyns, W. B., Reiner, O., Carrozzo, R. & Ledbetter, D. H. Lissencephaly. A human brain malformation associated with deletion of the LIS1 gene located at chromosome 17p13. JAMA 270, 2838–2842 (1993).
Vallee, R. B. & Tsai, J. W. The cellular roles of the lissencephaly gene LIS1, and what they tell us about brain development. Genes Dev. 20, 1384–1393 (2006).
Xiang, X., Roghi, C. & Morris, N. R. Characterization and localization of the cytoplasmic dynein heavy chain in Aspergillus nidulans. Proc. Natl Acad. Sci. USA 92, 9890–9894 (1995).
Geiser, J. R. et al. Saccharomyces cerevisiae genes required in the absence of the CIN8-encoded spindle motor act in functionally diverse mitotic pathways. Mol. Biol. Cell 8, 1035–1050 (1997).
Efimov, V. P. & Morris, N. R. The LIS1-related NUDF protein of Aspergillus nidulans interacts with the coiled-coil domain of the NUDE/RO11 protein. J. Cell Biol. 150, 681–688 (2000).
Feng, Y. et al. LIS1 regulates CNS lamination by interacting with mNudE, a central component of the centrosome. Neuron 28, 665–679 (2000).
Niethammer, M. et al. NUDEL is a novel Cdk5 substrate that associates with LIS1 and cytoplasmic dynein. Neuron 28, 697–711 (2000).
Sasaki, S. et al. A LIS1/NUDEL/cytoplasmic dynein heavy chain complex in the developing and adult nervous system. Neuron 28, 681–696 (2000).
Smith, D. S. et al. Regulation of cytoplasmic dynein behaviour and microtubule organization by mammalian Lis1. Nature Cell Biol. 2, 767–775 (2000).
Liang, Y. et al. Nudel functions in membrane traffic mainly through association with Lis1 and cytoplasmic dynein. J. Cell Biol. 164, 557–566 (2004).
Swan, A., Nguyen, T. & Suter, B. Drosophila Lissencephaly-1 functions with Bic-D and dynein in oocyte determination and nuclear positioning. Nature Cell Biol. 1, 444–449 (1999).
Han, G. et al. The Aspergillus cytoplasmic dynein heavy chain and NUDF localize to microtubule ends and affect microtubule dynamics. Curr. Biol. 11, 719–724 (2001).
Li, J., Lee, W. L. & Cooper, J. A. NudEL targets dynein to microtubule ends through LIS1. Nature Cell Biol. 7, 686–690 (2005).
Carvalho, P., Gupta, M. L. Jr, Hoyt, M. A. & Pellman, D. Cell cycle control of kinesin-mediated transport of Bik1 (CLIP-170) regulates microtubule stability and dynein activation. Dev. Cell 6, 815–829 (2004).
Coquelle, F. M. et al. LIS1, CLIP-170's key to the dynein/dynactin pathway. Mol. Cell. Biol. 22, 3089–3102 (2002).
Efimov, V. P. Roles of NUDE and NUDF proteins of Aspergillus nidulans: insights from intracellular localization and overexpression effects. Mol. Biol. Cell 14, 871–888 (2003).
Markus, S. M., Punch, J. J. & Lee, W. L. Motor- and tail-dependent targeting of dynein to microtubule plus ends and the cell cortex. Curr. Biol. 19, 196–205 (2009). This study in S. cerevisiae shows that, unlike full length dynein, LIS1-mediated microtubule plus end targeting of the dynein motor domain does not require NUDEL, suggesting that NUDEL is required only to prime dynein for LIS1 activity.
Feng, Y. & Walsh, C. A. Mitotic spindle regulation by Nde1 controls cerebral cortical size. Neuron 44, 279–293 (2004).
Shu, T. et al. Ndel1 operates in a common pathway with LIS1 and cytoplasmic dynein to regulate cortical neuronal positioning. Neuron 44, 263–277 (2004).
Siller, K. H. & Doe, C. Q. Lis1/dynactin regulates metaphase spindle orientation in Drosophila neuroblasts. Dev. Biol. 319, 1–9 (2008).
Tanaka, T. et al. Lis1 and doublecortin function with dynein to mediate coupling of the nucleus to the centrosome in neuronal migration. J. Cell Biol. 165, 709–721 (2004).
Tsai, J. W., Chen, Y., Kriegstein, A. R. & Vallee, R. B. LIS1 RNA interference blocks neural stem cell division, morphogenesis, and motility at multiple stages. J. Cell Biol. 170, 935–945 (2005).
Tsai, J. W., Bremner, K. H. & Vallee, R. B. Dual subcellular roles for LIS1 and dynein in radial neuronal migration in live brain tissue. Nature Neurosci. 10, 970–979 (2007). Through observations of migrating neurons in situ , the authors make the surprising observation that the nucleus frequently lags the movement of the centrosome, rather than being tightly coupled as had been thought previously. Dynein and LIS1 contribute to the continuous centrosome movement and to saltatory nuclear movements through separate mechanisms.
Gomes, E. R., Jani, S. & Gundersen, G. G. Nuclear movement regulated by Cdc42, MRCK, myosin, and actin flow establishes MTOC polarization in migrating cells. Cell 121, 451–463 (2005).
Dujardin, D. L. et al. A role for cytoplasmic dynein and LIS1 in directed cell movement. J. Cell Biol. 163, 1205–1211 (2003).
Shen, Y. et al. Nudel binds Cdc42GAP to modulate Cdc42 activity at the leading edge of migrating cells. Dev. Cell 14, 342–353 (2008).
Faulkner, N. E. et al. A role for the lissencephaly gene LIS1 in mitosis and cytoplasmic dynein function. Nature Cell Biol. 2, 784–791 (2000).
Cockell, M. M., Baumer, K. & Gonczy, P. lis-1 is required for dynein-dependent cell division processes in C. elegans embryos. J. Cell Sci. 117, 4571–4582 (2004).
Yang, Z. et al. Silencing mitosin induces misaligned chromosomes, premature chromosome decondensation before anaphase onset, and mitotic cell death. Mol. Cell. Biol. 25, 4062–4074 (2005).
Soukoulis, V. et al. Cytoplasmic LEK1 is a regulator of microtubule function through its interaction with the LIS1 pathway. Proc. Natl Acad. Sci. USA 102, 8549–8554 (2005).
Liang, Y. et al. Nudel modulates kinetochore association and function of cytoplasmic dynein in M phase. Mol. Biol. Cell 18, 2656–2666 (2007).
Vergnolle, M. A. & Taylor, S. S. Cenp-F links kinetochores to Ndel1/Nde1/Lis1/dynein microtubule motor complexes. Curr. Biol. 17, 1173–1179 (2007).
Mesngon, M. T. et al. Regulation of cytoplasmic dynein ATPase by Lis1. J. Neurosci. 26, 2132–2139 (2006).
Yamada, M. et al. LIS1 and NDEL1 coordinate the plus-end-directed transport of cytoplasmic dynein. EMBO J. 27, 2471–2483 (2008).
Mohler, J. & Wieschaus, E. F. Dominant maternal-effect mutations of Drosophila melanogaster causing the production of double-abdomen embryos. Genetics 112, 803–822 (1986).
Steward, R. & Nusslein-Volhard, C. The genetics of the dorsal-Bicaudal-D region of Drosophila melanogaster. Genetics 113, 665–678 (1986).
Bullock, S. L. & Ish-Horowicz, D. Conserved signals and machinery for RNA transport in Drosophila oogenesis and embryogenesis. Nature 414, 611–616 (2001).
Delanoue, R. & Davis, I. Dynein anchors its mRNA cargo after apical transport in the Drosophila blastoderm embryo. Cell 122, 97–106 (2005).
Navarro, C., Puthalakath, H., Adams, J. M., Strasser, A. & Lehmann, R. Egalitarian binds dynein light chain to establish oocyte polarity and maintain oocyte fate. Nature Cell Biol. 6, 427–435 (2004).
Hoogenraad, C. C. et al. Mammalian Golgi-associated Bicaudal-D2 functions in the dynein-dynactin pathway by interacting with these complexes. EMBO J. 20, 4041–4054 (2001).
Matanis, T. et al. Bicaudal-D regulates COPI-independent Golgi-ER transport by recruiting the dynein-dynactin motor complex. Nature Cell Biol. 4, 986–992 (2002).
Hoogenraad, C. C. et al. Bicaudal D induces selective dynein-mediated microtubule minus end-directed transport. EMBO J. 22, 6004–6015 (2003).
Larsen, K. S., Xu, J., Cermelli, S., Shu, Z. & Gross, S. P. BicaudalD actively regulates microtubule motor activity in lipid droplet transport. PLoS One 3, e3763 (2008).
Pare, C. & Suter, B. Subcellular localization of Bic-D::GFP is linked to an asymmetric oocyte nucleus. J. Cell Sci. 113, 2119–2127 (2000).
Fumoto, K., Hoogenraad, C. C. & Kikuchi, A. GSK-3β-regulated interaction of BICD with dynein is involved in microtubule anchorage at centrosome. EMBO J. 25, 5670–5682 (2006).
Oh, J. & Steward, R. Bicaudal-D is essential for egg chamber formation and cytoskeletal organization in drosophila oogenesis. Dev. Biol. 232, 91–104 (2001).
Dienstbier, M., Boehl, F., Li, X. & Bullock, S. L. Egalitarian is a selective RNA-binding protein linking mRNA localization signals to the dynein motor. Genes Dev. 23, 1546–1558 (2009). The authors show that the Bicaudal D binding partner Egalitarian directly binds localization signals on mRNA, and they propose a general framework for the contribution of Bicaudal D to dynein cargo binding.
Bullock, S. L., Nicol, A., Gross, S. P. & Zicha, D. Guidance of bidirectional motor complexes by mRNA cargoes through control of dynein number and activity. Curr. Biol. 16, 1447–1452 (2006).
Griffis, E. R., Stuurman, N. & Vale, R. D. Spindly, a novel protein essential for silencing the spindle assembly checkpoint, recruits dynein to the kinetochore. J. Cell Biol. 177, 1005–1015 (2007). Spindly is identified as a kinetochore-specific regulator of cytoplasmic dynein.
Yang, Z., Tulu, U. S., Wadsworth, P. & Rieder, C. L. Kinetochore dynein is required for chromosome motion and congression independent of the spindle checkpoint. Curr. Biol. 17, 973–980 (2007).
Li, Y., Yu, W., Liang, Y. & Zhu, X. Kinetochore dynein generates a poleward pulling force to facilitate congression and full chromosome alignment. Cell Res. 17, 701–712 (2007).
Tanaka, T. U. & Desai, A. Kinetochore-microtubule interactions: the means to the end. Curr. Opin. Cell Biol. 20, 53–63 (2008).
Gassmann, R. et al. A new mechanism controlling kinetochore-microtubule interactions revealed by comparison of two dynein-targeting components: SPDL-1 and the Rod/Zwilch/Zw10 complex. Genes Dev. 22, 2385–2399 (2008). The authors characterize the C. elegans homologue of Spindly and propose a model for how Spindly, RZZ and dynein regulate the maturation of microtubule–kinetochore attachments.
Yamamoto, T. G., Watanabe, S., Essex, A. & Kitagawa, R. SPDL-1 functions as a kinetochore receptor for MDF-1 in Caenorhabditis elegans. J. Cell Biol. 183, 187–194 (2008).
Howell, B. J. et al. Cytoplasmic dynein/dynactin drives kinetochore protein transport to the spindle poles and has a role in mitotic spindle checkpoint inactivation. J. Cell Biol. 155, 1159–1172 (2001).
Wojcik, E. et al. Kinetochore dynein: its dynamics and role in the transport of the Rough deal checkpoint protein. Nature Cell Biol. 3, 1001–1007 (2001). References 120 and 121 present the initial evidence that dynein transports SAC proteins away from the kinetochore, thus silencing the checkpoint, and that the RZZ complex is involved in this process.
Basto, R. et al. In vivo dynamics of the rough deal checkpoint protein during Drosophila mitosis. Curr. Biol. 14, 56–61 (2004).
Chan, Y. W. et al. Mitotic control of kinetochore-associated dynein and spindle orientation by human Spindly. J. Cell Biol. 185, 859–874 (2009).
Whyte, J. et al. Phosphorylation regulates targeting of cytoplasmic dynein to kinetochores during mitosis. J. Cell Biol. 183, 819–834 (2008).
Hirose, H. et al. Implication of ZW10 in membrane trafficking between the endoplasmic reticulum and Golgi. EMBO J. 23, 1267–1278 (2004).
Varma, D., Dujardin, D. L., Stehman, S. A. & Vallee, R. B. Role of the kinetochore/cell cycle checkpoint protein ZW10 in interphase cytoplasmic dynein function. J. Cell Biol. 172, 655–662 (2006).
Starr, D. A., Williams, B. C., Hays, T. S. & Goldberg, M. L. ZW10 helps recruit dynactin and dynein to the kinetochore. J. Cell Biol. 142, 763–774 (1998).
Bates, M., Huang, B., Dempsey, G. T. & Zhuang, X. Multicolor super-resolution imaging with photo-switchable fluorescent probes. Science 317, 1749–1753 (2007).
Huang, B., Wang, W., Bates, M. & Zhuang, X. Three-dimensional super-resolution imaging by stochastic optical reconstruction microscopy. Science 319, 810–813 (2008).
Betzig, E. et al. Imaging intracellular fluorescent proteins at nanometer resolution. Science 313, 1642–1645 (2006).
Shtengel, G. et al. Interferometric fluorescent super-resolution microscopy resolves 3D cellular ultrastructure. Proc. Natl Acad. Sci. USA 106, 3125–3130 (2009).
Reck-Peterson, S. L. & Vale, R. D. Molecular dissection of the roles of nucleotide binding and hydrolysis in dynein's AAA domains in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 101, 1491–1495 (2004).
Kon, T., Nishiura, M., Ohkura, R., Toyoshima, Y. Y. & Sutoh, K. Distinct functions of nucleotide-binding/hydrolysis sites in the four AAA modules of cytoplasmic dynein. Biochemistry 43, 11266–11274 (2004).
Cho, C., Reck-Peterson, S. L. & Vale, R. D. Regulatory ATPase sites of cytoplasmic dynein affect processivity and force generation. J. Biol. Chem. 283, 25839–25845 (2008).
Gee, M. A., Heuser, J. E. & Vallee, R. B. An extended microtubule-binding structure within the dynein motor domain. Nature 390, 636–639 (1997).
Burgess, S. A., Walker, M. L., Sakakibara, H., Knight, P. J. & Oiwa, K. Dynein structure and power stroke. Nature 421, 715–718 (2003).
Carter, A. P. et al. Structure and functional role of dynein's microtubule-binding domain. Science 322, 1691–1695 (2008).
Kon, T. et al. Helix sliding in the stalk coiled coil of dynein couples ATPase and microtubule binding. Nature Struct. Mol. Biol. 16, 325–333 (2009).
Gibbons, I. R. et al. The affinity of the dynein microtubule-binding domain is modulated by the conformation of its coiled-coil stalk. J. Biol. Chem. 280, 23960–23965 (2005).
Roberts, A. J. et al. AAA+ ring and linker swing mechanism in the dynein motor. Cell 136, 485–495 (2009). The authors use negative stain electron microscopy to map the position of the dynein linker domain and microtubule-binding stalk relative to the AAA ring in different nucleotide states and propose a mechanism for dynein motility based on movement of the linker across the face of the AAA ring.
Tai, C. Y., Dujardin, D. L., Faulkner, N. E. & Vallee, R. B. Role of dynein, dynactin, and CLIP-170 interactions in LIS1 kinetochore function. J. Cell Biol. 156, 959–968 (2002).
Stehman, S. A., Chen, Y., McKenney, R. J. & Vallee, R. B. NudE and NudEL are required for mitotic progression and are involved in dynein recruitment to kinetochores. J. Cell Biol. 178, 583–594 (2007).
Holleran, E. A., Tokito, M. K., Karki, S. & Holzbaur, E. L. Centractin (ARP1) associates with spectrin revealing a potential mechanism to link dynactin to intracellular organelles. J. Cell Biol. 135, 1815–1829 (1996).
Schafer, D. A., Gill, S. R., Cooper, J. A., Heuser, J. E. & Schroer, T. A. Ultrastructural analysis of the dynactin complex: an actin-related protein is a component of a filament that resembles F-actin. J. Cell Biol. 126, 403–412 (1994).
Eckley, D. M. et al. Analysis of dynactin subcomplexes reveals a novel actin-related protein associated with the arp1 minifilament pointed end. J. Cell Biol. 147, 307–320 (1999).
Garces, J. A., Clark, I. B., Meyer, D. I. & Vallee, R. B. Interaction of the p62 subunit of dynactin with Arp1 and the cortical actin cytoskeleton. Curr. Biol. 9, 1497–1500 (1999).
Vierula, P. J. & Mais, J. M. A gene required for nuclear migration in Neurospora crassa codes for a protein with cysteine-rich, LIM/RING-like domains. Mol. Microbiol. 24, 331–340 (1997).
Imai, H., Narita, A., Schroer, T. A. & Maeda, Y. Two-dimensional averaged images of the dynactin complex revealed by single particle analysis. J. Mol. Biol. 359, 833–839 (2006).
Moore, J. K., Li, J. & Cooper, J. A. Dynactin function in mitotic spindle positioning. Traffic 9, 510–527 (2008).
Kops, G. J. et al. ZW10 links mitotic checkpoint signaling to the structural kinetochore. J. Cell Biol. 169, 49–60 (2005).
Quintyne, N. J. et al. Dynactin is required for microtubule anchoring at centrosomes. J. Cell Biol. 147, 321–334 (1999).
King, S. J., Brown, C. L., Maier, K. C., Quintyne, N. J. & Schroer, T. A. Analysis of the dynein-dynactin interaction in vitro and in vivo. Mol. Biol. Cell 14, 5089–5097 (2003).
Kim, M. H. et al. The structure of the N-terminal domain of the product of the lissencephaly gene Lis1 and its functional implications. Structure 12, 987–998 (2004).
Tarricone, C. et al. Coupling PAF signaling to dynein regulation: structure of LIS1 in complex with PAF-acetylhydrolase. Neuron 44, 809–821 (2004).
Derewenda, U. et al. The structure of the coiled-coil domain of ndel1 and the basis of its interaction with lis1, the causal protein of miller-dieker lissencephaly. Structure 15, 1467–1481 (2007).
Yan, X. et al. Human Nudel and NudE as regulators of cytoplasmic dynein in poleward protein transport along the mitotic spindle. Mol. Cell. Biol. 23, 1239–1250 (2003).
Hebbar, S. et al. Lis1 and Ndel1 influence the timing of nuclear envelope breakdown in neural stem cells. J. Cell Biol. 182, 1063–1071 (2008).
Hattori, M., Adachi, H., Tsujimoto, M., Arai, H. & Inoue, K. Miller-Dieker lissencephaly gene encodes a subunit of brain platelet-activating factor acetylhydrolase. Nature 370, 216–218 (1994).
Oh, J., Baksa, K. & Steward, R. Functional domains of the Drosophila bicaudal-D protein. Genetics 154, 713–724 (2000).
Stuurman, N. et al. Interactions between coiled-coil proteins: Drosophila lamin Dm0 binds to the bicaudal-D protein. Eur. J. Cell Biol. 78, 278–287 (1999).
Wanschers, B. F. et al. A role for the Rab6B Bicaudal-D1 interaction in retrograde transport in neuronal cells. Exp. Cell Res. 313, 3408–3420 (2007).
Siller, K. H., Serr, M., Steward, R., Hays, T. S. & Doe, C. Q. Live imaging of Drosophila brain neuroblasts reveals a role for Lis1/dynactin in spindle assembly and mitotic checkpoint control. Mol. Biol. Cell 16, 5127–5140 (2005).
Dzhindzhev, N. S., Rogers, S. L., Vale, R. D. & Ohkura, H. Distinct mechanisms govern the localisation of Drosophila CLIP-190 to unattached kinetochores and microtubule plus-ends. J. Cell Sci. 118, 3781–3790 (2005).
Acknowledgements
We thank S. Reck-Peterson, A. Carter, N. Bradshaw and E. Griffis for helpful discussions and editorial comments and apologize to those authors whose work we could not cite owing to space limitations. This work was supported by the National Institutes of Health (grant number 38499, R.D.V.), the National Science Foundation (J.R.K) and the Howard Hughes Medical Institute.
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Glossary
- Axoneme
-
The bundled microtubule structure at the centre of eukaryotic cilia and flagella. Coordinated binding and release of the axonemal dyneins slides the microtubules relative to each other. This causes the axoneme to bend and drives ciliary and flagellar beating. Axonemes function as tracks for the motors involved in intraflagellar transport.
- AAA+ ATPase
-
(ATPase associated with various cellular activities). A large family of ATPases, the functions of which are diverse, with many involved in the conformational remodelling of other proteins and complexes. AAA+ ATPases contain one or two characteristic ATP-binding domains, with additional function-specific domains. These AAA modules usually function as hexameric rings.
- Coiled coil
-
A common structural motif in proteins, consisting of two or more α-helices that twist around each other and bury hydrophobic residues in the interface and form an overall rod-like structure.
- Optical trap
-
An instrument that uses a focused laser beam to hold, move and monitor the position of microscopic dielectric objects. Optical traps can be used to measure the force production and nanoscale movements of molecular motors that have been conjugated to dielectric objects such as latex beads.
- Protofilament
-
The end-to-end arrangement of tubulin dimers along the long axis of microtubules. Microtubules most commonly are composed of thirteen protofilaments.
- Astral microtubule
-
A microtubule that radiates from the mitotic spindle poles to the cell cortex. Astral microtubules are involved in the positioning and alignment of the spindle poles during cell division.
- Hypha
-
The branching filament that is the main mode of vegetative growth for filamentous fungi. During hyphal growth, hyphae elongate from their tips and position newly formed nuclei along the length of the new growth.
- Cytoskeleton-associated protein Gly-rich
-
(Cap-Gly). A domain found in several microtubule-associated proteins, which binds the EEY/F motif found at the carboxyl terminus of α-tubulin and several microtubule plus end-associated proteins.
- GTPase-activating protein
-
A protein that stimulates the intrinsic activity of a GTPase to hydrolyse GTP to GDP.
- CopII coat
-
A complex consisting of SEC13, SEC23, SEC24 and SEC31. This coat complex functions in anterograde transport from the endoplasmic reticulum to the Golgi.
- GTPase effector
-
A protein that binds specifically to the GTP-bound conformation of a GTPase.
- Kinetochore
-
A large multiprotein complex that assembles onto the centromere of the chromosome and links it to the microtubules of the mitotic spindle. The kinetochore is also a signalling centre for many of the proteins that control the progression of mitosis.
- WD40 repeat
-
A motif of 40 amino acids that contains a Trp and Asp dipeptide at its carboxyl terminus. This domain is found in many functionally diverse proteins and often mediates protein–protein interactions.
- Centrosome
-
The principal microtubule-organizing centre of animal cells, an organelle that contains the centrioles and that anchors the minus end of microtubules.
- Spindle assembly checkpoint
-
The mitotic signalling pathway that prevents chromosome separation until all kinetochores have formed microtubule attachments. The proteins involved in this pathway have to be localized at the kinetochore to ensure chromosome segregation, and their physical removal from attached kinetochores by dynein silences their signalling and allows chromosome separation to begin.
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Kardon, J., Vale, R. Regulators of the cytoplasmic dynein motor. Nat Rev Mol Cell Biol 10, 854–865 (2009). https://doi.org/10.1038/nrm2804
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DOI: https://doi.org/10.1038/nrm2804
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