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Dynactin

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Quaternary structure of dynactin

Dynactin is a 23 subunit protein complex that acts as a co-factor for the microtubule motor cytoplasmic dynein-1. It is built around a short filament of actin related protein-1 (Arp1).[1][2]

Discovery

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Dynactin was identified as an activity that allowed purified cytoplasmic dynein to move membrane vesicles along microtubules in vitro.[3] It was shown to be a multiprotein complex and named "dynactin" because of its role in dynein activation.[4]

The main features of dynactin were visualized by quick-freeze, deep-etch, rotary shadow electron microscopy. It appears as a short filament, 37-nm in length, which resembles F-actin, plus a thinner, laterally oriented arm.[5] Antibody labelling was used to map the location of the dynactin subunits.[5][6]

Structure

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Dynactin consists of three major structural domains: (1) sidearm-shoulder: DCTN1/p150Glued, DCTN2/p50/dynamitin, DCTN3/p24/p22;(2)the Arp1 filament: ACTR1A/Arp1/centractin, actin, CapZ; and (3) the pointed end complex: Actr10/Arp11, DCTN4/p62, DCTN5/p25, and DCTN6/p27.[1]

A 4Å cryo-EM structure of dynactin [7] revealed that its filament contains eight Arp1 molecules, one β-actin and one Arp11. In the pointed end complex p62/DCTN4 binds to Arp11 and β-actin and p25 and p27 bind both p62 and Arp11. At the barbed end the capping protein (CapZαβ) binds the Arp1 filament in the same way that it binds actin, although with more charge complementarity, explaining why it binds dynactin more tightly than actin.[8]

The shoulder contains two copies of p150Glued/DCTN1, four copies of p50/DCTN2 and two copies of p24/DCTN3.[1] These proteins form long bundles of alpha helices, which wrap over each other and contact the Arp1 filament.[7] The N-termini of p50/DCTN2 emerge from the shoulder and coat the filament, providing a mechanism for controlling the filament length.[7] The C-termini of the p150Glued/DCTN1 dimer are embedded in the shoulder, whereas the N-terminal 1227 amino acids form the projecting arm. The arm consists of an N-terminal CAPGly domain which can bind the C-terminal tails of microtubules and the microtubule plus end binding protein EB1. This is followed by a basic region, also involved in microtubule binding, a folded-back coiled coil (CC1), the intercoiled domain (ICD) and a second coiled coil domain (CC2).[7] The p150Glued arm can dock into against the side of the Arp1 filament and pointed end complex.[7]

DCTN2 (dynamitin) is also involved in anchoring microtubules to centrosomes and may play a role in synapse formation during brain development.[9] Arp1 has been suggested as the domain for dynactin binding to membrane vesicles (such as Golgi or late endosome) through its association with β-spectrin.[10][11][12][13] The pointed end complex (PEC) has been shown to be involved in selective cargo binding. PEC subunits p62/DCTN4 and Arp11/Actr10 are essential for dynactin complex integrity and dynactin/dynein targeting to the nuclear envelope before mitosis.[14][15][16] Actr10 along with Drp1 (Dynamin related protein 1) have been documented as vital to the attachment of mitochondria to the dynactin complex.[17] Dynactin p25/DCTN5 and p27/DCTN6 are not essential for dynactin complex integrity, but are required for early and recycling endosome transport during the interphase and regulation of the spindle assembly checkpoint in mitosis.[16][18][19]

Interaction with dynein

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Dynein and dynactin were reported to interact directly by the binding of dynein intermediate chains with p150Glued.[20] The affinity of this interaction is around 3.5μM.[21] Dynein and dynactin do not run together in a sucrose gradient, but can be induced to form a tight complex in the presence of the N-terminal 400 amino acids of Bicaudal D2 (BICD2), a cargo adaptor that links dynein and dynactin to Golgi derived vesicles.[22] In the presence of BICD2, dynactin binds to dynein and activates it to move for long distances along microtubules.[23][24]

A cryo-EM structure of dynein, dynactin and BICD2 [7] showed that the BICD2 coiled coil runs along the dynactin filament. The tail of dynein also binds to the Arp1 filament, sitting in the equivalent site that myosin uses to bind actin. The contacts between the dynein tail and dynactin all involve BICD, explaining why it is needed to bring them together. The dynein/dynactin/BICD2 (DDB) complex has also been observed, by negative stain EM, on microtubules. This shows that the cargo (Rab6) binding end of BICD2 extends out through the pointed end complex at the opposite end away from the dynein motor domains.[25]

Functions

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Dynactin is often essential for dynein activity[1][3] and can be thought of as a "dynein receptor"[20] that modulates binding of dynein to cell organelles which are to be transported along microtubules.[26][27] Dynactin also enhances the processivity of cytoplasmic dynein[28] and kinesin-2 motors.[29] Dynactin is involved in various processes like chromosome alignment and spindle organization[30] in cell division.[31] Dynactin contributes to mitotic spindle pole focusing through its binding to nuclear mitotic apparatus protein (NuMA).[32][33] Dynactin also targets to the kinetochore through binding between DCTN2/dynamitin and zw10 and has a role in mitotic spindle checkpoint inactivation.[34][35] During prometaphase, dynactin also helps target polo-like kinase 1 (Plk1) to kinetochores through cyclin dependent kinase 1 (Cdk1)-phosphorylated DCTN6/p27, which is involved in proper microtubule-kinetochore attachment and recruitment of spindle assembly checkpoint protein Mad1.[19] In addition, dynactin has been shown to play an essential role in maintaining nuclear position in Drosophila,[36] zebrafish[37] or in different fungi.[38][39] Dynein and dynactin concentrate on the nuclear envelope during the prophase and facilitate nuclear envelope breakdown via its DCTN4/p62 and Arp11 subunits.[16][14] Dynactin is also required for microtubule anchoring at centrosomes and centrosome integrity.[40] Destabilization of the centrosomal pool of dynactin also causes abnormal G1 centriole separation and delayed entry into S phase, suggesting that dynactin contributes to the recruitment of important cell cycle regulators to centrosomes.[41] In addition to transport of various organelles in the cytoplasm, dynactin also links kinesin II to organelles.[42]

See also

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References

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  1. ^ a b c d Schroer TA (November 2004). "Dynactin". Annual Review of Cell and Developmental Biology. 20: 759–79. doi:10.1146/annurev.cellbio.20.012103.094623. PMID 15473859.
  2. ^ Carter AP, Diamant AG, Urnavicius L (April 2016). "How dynein and dynactin transport cargos: a structural perspective". Current Opinion in Structural Biology. 37: 62–70. doi:10.1016/j.sbi.2015.12.003. PMID 26773477.
  3. ^ a b Schroer TA, Sheetz MP (December 1991). "Two activators of microtubule-based vesicle transport". The Journal of Cell Biology. 115 (5): 1309–18. doi:10.1083/jcb.115.5.1309. PMC 2289226. PMID 1835460.
  4. ^ Gill SR, Schroer TA, Szilak I, Steuer ER, Sheetz MP, Cleveland DW (December 1991). "Dynactin, a conserved, ubiquitously expressed component of an activator of vesicle motility mediated by cytoplasmic dynein". The Journal of Cell Biology. 115 (6): 1639–50. doi:10.1083/jcb.115.6.1639. PMC 2289205. PMID 1836789.
  5. ^ a b Schafer DA, Gill SR, Cooper JA, Heuser JE, Schroer TA (July 1994). "Ultrastructural analysis of the dynactin complex: an actin-related protein is a component of a filament that resembles F-actin". The Journal of Cell Biology. 126 (2): 403–12. doi:10.1083/jcb.126.2.403. PMC 2200042. PMID 7518465.
  6. ^ Eckley DM, Gill SR, Melkonian KA, Bingham JB, Goodson HV, Heuser JE, Schroer TA (October 1999). "Analysis of dynactin subcomplexes reveals a novel actin-related protein associated with the arp1 minifilament pointed end". The Journal of Cell Biology. 147 (2): 307–20. doi:10.1083/jcb.147.2.307. PMC 2174220. PMID 10525537.
  7. ^ a b c d e f Urnavicius L, Zhang K, Diamant AG, Motz C, Schlager MA, Yu M, Patel NA, Robinson CV, Carter AP (March 2015). "The structure of the dynactin complex and its interaction with dynein". Science. 347 (6229): 1441–1446. Bibcode:2015Sci...347.1441U. doi:10.1126/science.aaa4080. PMC 4413427. PMID 25814576.
  8. ^ Cheong FK, Feng L, Sarkeshik A, Yates JR, Schroer TA (July 2014). "Dynactin integrity depends upon direct binding of dynamitin to Arp1". Molecular Biology of the Cell. 25 (14): 2171–80. doi:10.1091/mbc.E14-03-0842. PMC 4091830. PMID 24829381.
  9. ^ Uetake Y, Terada Y, Matuliene J, Kuriyama R (May 2004). "Interaction of Cep135 with a p50 dynactin subunit in mammalian centrosomes". Cell Motility and the Cytoskeleton. 58 (1): 53–66. doi:10.1002/cm.10175. PMID 14983524.
  10. ^ Holleran EA, Tokito MK, Karki S, Holzbaur EL (December 1996). "Centractin (ARP1) associates with spectrin revealing a potential mechanism to link dynactin to intracellular organelles". The Journal of Cell Biology. 135 (6 Pt 2): 1815–29. doi:10.1083/jcb.135.6.1815. PMC 2133946. PMID 8991093.
  11. ^ Holleran EA, Ligon LA, Tokito M, Stankewich MC, Morrow JS, Holzbaur EL (September 2001). "beta III spectrin binds to the Arp1 subunit of dynactin". The Journal of Biological Chemistry. 276 (39): 36598–605. doi:10.1074/jbc.M104838200. PMID 11461920.
  12. ^ Muresan V, Stankewich MC, Steffen W, Morrow JS, Holzbaur EL, Schnapp BJ (January 2001). "Dynactin-dependent, dynein-driven vesicle transport in the absence of membrane proteins: a role for spectrin and acidic phospholipids". Molecular Cell. 7 (1): 173–83. doi:10.1016/S1097-2765(01)00165-4. PMID 11172722.
  13. ^ Johansson M, Rocha N, Zwart W, Jordens I, Janssen L, Kuijl C, Olkkonen VM, Neefjes J (February 2007). "Activation of endosomal dynein motors by stepwise assembly of Rab7-RILP-p150Glued, ORP1L, and the receptor betalll spectrin". The Journal of Cell Biology. 176 (4): 459–71. doi:10.1083/jcb.200606077. PMC 2063981. PMID 17283181.
  14. ^ a b Salina D, Bodoor K, Eckley DM, Schroer TA, Rattner JB, Burke B (January 2002). "Cytoplasmic dynein as a facilitator of nuclear envelope breakdown". Cell. 108 (1): 97–107. doi:10.1016/S0092-8674(01)00628-6. PMID 11792324. S2CID 18798861.
  15. ^ Zhang J, Wang L, Zhuang L, Huo L, Musa S, Li S, Xiang X (July 2008). "Arp11 affects dynein-dynactin interaction and is essential for dynein function in Aspergillus nidulans". Traffic. 9 (7): 1073–87. doi:10.1111/j.1600-0854.2008.00748.x. PMC 2586032. PMID 18410488.
  16. ^ a b c Yeh TY, Quintyne NJ, Scipioni BR, Eckley DM, Schroer TA (October 2012). "Dynactin's pointed-end complex is a cargo-targeting module". Molecular Biology of the Cell. 23 (19): 3827–37. doi:10.1091/mbc.E12-07-0496. PMC 3459859. PMID 22918948.
  17. ^ Catherine Drerup, Amy Herbert, Kelly Monk, Alex Nechiporuk, "Regulation of mitochondria-dynactin interaction and mitochondrial retrograde transport in axons"
  18. ^ Zhang J, Yao X, Fischer L, Abenza JF, Peñalva MA, Xiang X (June 2011). "The p25 subunit of the dynactin complex is required for dynein-early endosome interaction". The Journal of Cell Biology. 193 (7): 1245–55. doi:10.1083/jcb.201011022. PMC 3216330. PMID 21708978.
  19. ^ a b Yeh TY, Kowalska AK, Scipioni BR, Cheong FK, Zheng M, Derewenda U, Derewenda ZS, Schroer TA (April 2013). "Dynactin helps target Polo-like kinase 1 to kinetochores via its left-handed beta-helical p27 subunit". The EMBO Journal. 32 (7): 1023–35. doi:10.1038/emboj.2013.30. PMC 3616283. PMID 23455152.
  20. ^ a b Vaughan KT, Vallee RB (December 1995). "Cytoplasmic dynein binds dynactin through a direct interaction between the intermediate chains and p150Glued". The Journal of Cell Biology. 131 (6 Pt 1): 1507–16. doi:10.1083/jcb.131.6.1507. PMC 2120689. PMID 8522607.
  21. ^ Morgan JL, Song Y, Barbar E (November 2011). "Structural dynamics and multiregion interactions in dynein-dynactin recognition". The Journal of Biological Chemistry. 286 (45): 39349–59. doi:10.1074/jbc.M111.296277. PMC 3234759. PMID 21931160.
  22. ^ Splinter D, Razafsky DS, Schlager MA, Serra-Marques A, Grigoriev I, Demmers J, Keijzer N, Jiang K, Poser I, Hyman AA, Hoogenraad CC, King SJ, Akhmanova A (November 2012). "BICD2, dynactin, and LIS1 cooperate in regulating dynein recruitment to cellular structures". Molecular Biology of the Cell. 23 (21): 4226–41. doi:10.1091/mbc.E12-03-0210. PMC 3484101. PMID 22956769.
  23. ^ Schlager MA, Hoang HT, Urnavicius L, Bullock SL, Carter AP (September 2014). "In vitro reconstitution of a highly processive recombinant human dynein complex". The EMBO Journal. 33 (17): 1855–68. doi:10.15252/embj.201488792. PMC 4158905. PMID 24986880.
  24. ^ McKenney RJ, Huynh W, Tanenbaum ME, Bhabha G, Vale RD (July 2014). "Activation of cytoplasmic dynein motility by dynactin-cargo adapter complexes". Science. 345 (6194): 337–41. Bibcode:2014Sci...345..337M. doi:10.1126/science.1254198. PMC 4224444. PMID 25035494.
  25. ^ Chowdhury S, Ketcham SA, Schroer TA, Lander GC (April 2015). "Structural organization of the dynein-dynactin complex bound to microtubules". Nature Structural & Molecular Biology. 22 (4): 345–7. doi:10.1038/nsmb.2996. PMC 4385409. PMID 25751425.
  26. ^ Waterman-Storer CM, Karki SB, Kuznetsov SA, Tabb JS, Weiss DG, Langford GM, Holzbaur EL (October 1997). "The interaction between cytoplasmic dynein and dynactin is required for fast axonal transport". Proceedings of the National Academy of Sciences of the United States of America. 94 (22): 12180–5. Bibcode:1997PNAS...9412180W. doi:10.1073/pnas.94.22.12180. PMC 23743. PMID 9342383.
  27. ^ McGrail M, Gepner J, Silvanovich A, Ludmann S, Serr M, Hays TS (October 1995). "Regulation of cytoplasmic dynein function in vivo by the Drosophila Glued complex". The Journal of Cell Biology. 131 (2): 411–25. doi:10.1083/jcb.131.2.411. PMC 2199972. PMID 7593168.
  28. ^ King SJ, Schroer TA (January 2000). "Dynactin increases the processivity of the cytoplasmic dynein motor". Nature Cell Biology. 2 (1): 20–4. doi:10.1038/71338. PMID 10620802. S2CID 20349195.
  29. ^ Berezuk MA, Schroer TA (February 2007). "Dynactin enhances the processivity of kinesin-2". Traffic. 8 (2): 124–9. doi:10.1111/j.1600-0854.2006.00517.x. PMID 17181772. S2CID 46446471.
  30. ^ Echeverri CJ, Paschal BM, Vaughan KT, Vallee RB (February 1996). "Molecular characterization of the 50-kD subunit of dynactin reveals function for the complex in chromosome alignment and spindle organization during mitosis". The Journal of Cell Biology. 132 (4): 617–33. doi:10.1083/jcb.132.4.617. PMC 2199864. PMID 8647893.
  31. ^ Karki S, Holzbaur EL (February 1999). "Cytoplasmic dynein and dynactin in cell division and intracellular transport". Current Opinion in Cell Biology. 11 (1): 45–53. doi:10.1016/S0955-0674(99)80006-4. PMID 10047518.
  32. ^ Gaglio T, Saredi A, Bingham JB, Hasbani MJ, Gill SR, Schroer TA, Compton DA (October 1996). "Opposing motor activities are required for the organization of the mammalian mitotic spindle pole". The Journal of Cell Biology. 135 (2): 399–414. doi:10.1083/jcb.135.2.399. PMC 2121053. PMID 8896597.
  33. ^ Merdes A, Heald R, Samejima K, Earnshaw WC, Cleveland DW (May 2000). "Formation of spindle poles by dynein/dynactin-dependent transport of NuMA". The Journal of Cell Biology. 149 (4): 851–62. doi:10.1083/jcb.149.4.851. PMC 2174573. PMID 10811826.
  34. ^ Howell BJ, McEwen BF, Canman JC, Hoffman DB, Farrar EM, Rieder CL, Salmon ED (December 2001). "Cytoplasmic dynein/dynactin drives kinetochore protein transport to the spindle poles and has a role in mitotic spindle checkpoint inactivation". The Journal of Cell Biology. 155 (7): 1159–72. doi:10.1083/jcb.200105093. PMC 2199338. PMID 11756470.
  35. ^ Starr DA, Williams BC, Hays TS, Goldberg ML (August 1998). "ZW10 helps recruit dynactin and dynein to the kinetochore". The Journal of Cell Biology. 142 (3): 763–74. doi:10.1083/jcb.142.3.763. PMC 2148168. PMID 9700164.
  36. ^ Whited JL, Cassell A, Brouillette M, Garrity PA (October 2004). "Dynactin is required to maintain nuclear position within postmitotic Drosophila photoreceptor neurons". Development. 131 (19): 4677–86. doi:10.1242/dev.01366. PMC 2714772. PMID 15329347.
  37. ^ Tsujikawa M, Omori Y, Biyanwila J, Malicki J (September 2007). "Mechanism of positioning the cell nucleus in vertebrate photoreceptors". Proceedings of the National Academy of Sciences of the United States of America. 104 (37): 14819–24. Bibcode:2007PNAS..10414819T. doi:10.1073/pnas.0700178104. PMC 1976238. PMID 17785424.
  38. ^ Xiang X, Han G, Winkelmann DA, Zuo W, Morris NR (May 2000). "Dynamics of cytoplasmic dynein in living cells and the effect of a mutation in the dynactin complex actin-related protein Arp1". Current Biology. 10 (10): 603–6. doi:10.1016/S0960-9822(00)00488-7. PMID 10837229. S2CID 29254054.
  39. ^ Bruno KS, Tinsley JH, Minke PF, Plamann M (May 1996). "Genetic interactions among cytoplasmic dynein, dynactin, and nuclear distribution mutants of Neurospora crassa". Proceedings of the National Academy of Sciences of the United States of America. 93 (10): 4775–80. Bibcode:1996PNAS...93.4775B. doi:10.1073/pnas.93.10.4775. PMC 39355. PMID 8643479.
  40. ^ Quintyne NJ, Gill SR, Eckley DM, Crego CL, Compton DA, Schroer TA (October 1999). "Dynactin is required for microtubule anchoring at centrosomes". The Journal of Cell Biology. 147 (2): 321–34. doi:10.1083/jcb.147.2.321. PMC 2174233. PMID 10525538.
  41. ^ Quintyne NJ, Schroer TA (October 2002). "Distinct cell cycle-dependent roles for dynactin and dynein at centrosomes". The Journal of Cell Biology. 159 (2): 245–54. doi:10.1083/jcb.200203089. PMC 2173046. PMID 12391026.
  42. ^ Deacon SW, Serpinskaya AS, Vaughan PS, Lopez Fanarraga M, Vernos I, Vaughan KT, Gelfand VI (February 2003). "Dynactin is required for bidirectional organelle transport". The Journal of Cell Biology. 160 (3): 297–301. doi:10.1083/jcb.200210066. PMC 2172679. PMID 12551954.

Further reading

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This article incorporates text from the public domain Pfam and InterPro: IPR008603
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