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Dynactin or Dynein activator complex is a multi-subunit protein found in eukaryotic cells that aids in bidirectional intracellular transport by binding to dynein and kinesin-2 and linking them to the organelle or vesicle to be transported.[1][2]


Structure and mechanism of action

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Dynactin
Identifiers
SymbolDynactin
PfamPF12455
InterProIPR022157
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Dynamitin
Identifiers
SymbolDynamitin
PfamPF04912
InterProIPR006996
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Dynactin subunit p22
Identifiers
SymbolDynactin_p22
PfamPF07426
InterProIPR009991
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Dynactin p62 family
Identifiers
SymbolDynactin_p62
PfamPF05502
InterProIPR008603
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Dynactin consists of many subunits of which the p150Glued protein (encoded by the DCTN1 gene) is the largest and has been found to be essential for function.[1] This structure of dynactin is highly conserved in vertebrates. There are three isoforms encoded by a single p150Glued gene.[3] The dynactin complex visualized by deepetch electron microscopy appears as a short filament 37-nm in length, which resembles F-actin, plus a thinner, laterally oriented arm that terminates in two globular heads.[4]

The dynactin complex consists of three major structural domains: (1) sidearm-shoulder: DCTN1, DCTN2/dynamitin, DCTN3/p22/p24;(2)the Arp1 rod: Arp1/centractin, actin, CapZ; and (3) the pointed end complex: Actr10/Arp11, DCTN4/p62, DCTN5/p25, and DCTN6/p27.[5] DCTN2 (dynamitin) is also involved in anchoring microtubules to centrosomes and may play a role in synapse formation during brain development.[6] DCTN4 (p62) binds directly to the Arp1 subunit of dynactin.[7][8] 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.[9][10][11][12] 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.[13][14][15] 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.[15][16][17]

A 4Å cryo-EM structure of dynactin [18] revealed that its filament contains a top and bottom protofilament. There are five Arp1 molecules in the top and three Arp1, one β-actin and one Arp11 in the bottom protofilament. 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. The shoulder contains two long arms, each made of two copies of p50/DCTN2 and one copy of p24/DCTN3, which wrap over each other and contact the Arp1 filament. The N-termini of p50/DCTN2 emerge from the shoulder and coat the filament. The C-termini of p150Glued/DCTN1 are embedded in the shoulder. The N-terminal 1227 amino acids form a long projection consisting of a folded back coiled coil (CC1), the intercoiled domain (ICD) and a second coiled coil domain (CC2). p150Glued can dock into against the side of the Arp1 filament and pointed end complex. The N-terminal CAPGly and basic domains of p150Glued were not observed in the structure.

Dynein and dynactin were reported to bind interact directly by the binding of dynein intermediate chains with p150Glued.[19] The affinity of this interaction is around 3.5μM .[20] 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.[21] In the presence of BICD2, dynactin binds to dynein and activates it to move for long distances along microtubules. .[22][23] A cryo-EM structure of dynein, dynactin and BICD2 [18] 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.[24]

Functions

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Dynactin is often essential for dynein activity[1][25] and can be thought of as a "dynein receptor"[19] 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.[17] 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.[15][40] Dynactin is also required for microtubule anchoring at centrosomes and centrosome integrity.[41] 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.[42] In addition to transport of various organelles in the cytoplasm, dynactin also links kinesin II to organelles.[2]

See also

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References

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  1. ^ a b c Schroer Trina A (November 2004). "Annual Review of Cell and Developmental Biology". Annual Review of Cell and Developmental Biology. 20: 759–779. doi:10.1146/annurev.cellbio.20.012103.094623. PMID 15473859.
  2. ^ a b Deacon Sean W; Serpinskaya Anna S; Vaughan Patricia S; Fanarraga Monica Lopez; Vernos Isabelle; Vaughan Kevin T; Gelfand Vladimir I (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.
  3. ^ Gill SR, Schroer TA, Szilak I, Steuer ER, Sheetz MP, Cleveland DW (1991). "Dynactin, a conserved, ubiquitously expressed component of an activator of vesicle motility mediated by cytoplasmic dynein". The Journal of Cell Biology. 115 (6): 1639–1650. doi:10.1083/jcb.115.6.1639. PMC 2289205. PMID 1836789.
  4. ^ Schafer, DA; Gill, SR; Cooper, JA; Heuser, JE; Schroer, TA (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): 403–412. doi:10.1083/jcb.126.2.403. PMC 2200042. PMID 7518465.
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  14. ^ 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.
  15. ^ 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.
  16. ^ Zhang, J; Yao, X; Fischer, L; Abenza, JF; Peñalva, MA; Xiang, X (Jun 27, 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.
  17. ^ a b Yeh, TY; Kowalska, AK; Scipioni, BR; Cheong, FK; Zheng, M; Derewenda, U; Derewenda, ZS; Schroer, TA (Apr 3, 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.
  18. ^ a b Urnavicius, L.; Zhang, K. (2014). "The structure of the dynactin complex and its interaction with dynein". Science. 347 (6229): 1441–6. doi:10.1126/science.aaa4080. PMC 4413427. PMID 25814576.
  19. ^ a b Vaughan KT, Vallee RB (1995). "Cytoplasmic dynein binds dynactin through a direct interaction between the intermediate chains and p150Glued". The Journal of Cell Biology. 131 (6 Pt 1): 1507–1516. doi:10.1083/jcb.131.6.1507. PMC 2120689. PMID 8522607.
  20. ^ Morgan JL, Song Y, Barbar E (2011). "Structural dynamics and multiregion interactions in dynein-dynactin recognition". J Biol Chem. 286: 39349–59. doi:10.1074/jbc.M111.296277. PMC 3234759. PMID 21931160.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  21. ^ 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 (2012). "BICD2, dynactin, and LIS1 cooperate in regulating dynein recruitment to cellular structures". Mol Biol Cell. 23: 4226–41. doi:10.1091/mbc.E12-03-0210. PMC 3484101. PMID 22956769.
  22. ^ Schlager MA, Hoang HT, Urnavicius L, Bullock SL, Carter AP (2014). "In vitro reconstitution of a highly processive recombinant human dynein complex". EMBO J. 33: 1855–68. doi:10.15252/embj.201488792. PMC 4158905. PMID 24986880.
  23. ^ McKenney RJ, Huynh W, Tanenbaum ME, Bhabha G, Vale RD (2014). "Activation of cytoplasmic dynein motility by dynactin-cargo adapter complexes". Science. 345: 337–41. doi:10.1126/science.1254198. PMC 4224444. PMID 25035494.
  24. ^ Chowdhury S, Ketcham SA, Schroer TA, Lander GC (2015). "Structural organization of the dynein-dynactin complex bound to microtubules". Nat Struct Mol Biol. 22: 345–7. doi:10.1038/nsmb.2996. PMC 4385409. PMID 25751425.
  25. ^ Schroer, TA; Sheetz, MP. (1991). "Two activators of microtubule-based vesicle transport". J Cell Biol. 115 (5): 1309–18. doi:10.1083/jcb.115.5.1309. PMC 2289226. PMID 1835460.
  26. ^ Waterman-Storer, C.M.; Karki, S.B.; Kuznetsov, S.A.; Tabb, J.S.; Weiss, D.G.; Langford, G.M.; Holzbaur, E.L. (1997). "The interaction between cytoplasmic dynein and dynactin is required for fast axonal transport". Proc. Natl. Acad. Sci. USA. 94 (22): 12180–12185. doi:10.1073/pnas.94.22.12180. PMC 23743. PMID 9342383.
  27. ^ McGrail, M; Gepner, J; Silvanovich, A; Ludmann, S; Serr, M; Hays, TS. (1995). "Regulation of cytoplasmic dynein function in vivo by the Drosophila Glued complex". J Cell Biol. 131 (2): 411–25. doi:10.1083/jcb.131.2.411. PMC 2199972. PMID 7593168.
  28. ^ King, SJ; Schroer, TA (2000). "Dynactin increases the processivity of the cytoplasmic dynein motor". Nature Cell Biology. 2 (1): 20–24. doi:10.1038/71338. PMID 10620802.
  29. ^ Berezuk, MA; Schroer, TA (2007). "Dynactin Enhances the Processivity of Kinesin-2". Traffic. 8 (2): 124–129. doi:10.1111/j.1600-0854.2006.00517.x. PMID 17181772.
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  31. ^ Karki Sher; Holzbaur Erika LF (1 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 (1996). "Opposing motor activities are required for the organization of the mammalian mitotic spindle pole". J. Cell Biol. 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. (2000). "Formation of Spindle Poles by Dynein/Dynactin-Dependent Transport of Numa". J Cell Biol. 149 (4): 851–62. doi:10.1083/jcb.149.4.851. PMC 2174573. PMID 10811826.
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  35. ^ Starr, DA; Williams, BC; Hays, TS; Goldberg, ML. (1998). "ZW10 Helps Recruit Dynactin and Dynein to the Kinetochore". J Cell Biol. 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. (2007). "Mechanism of positioning the cell nucleus in vertebrate photoreceptors". Proc Natl Acad Sci U S A. 104 (37): 14819–24. doi:10.1073/pnas.0700178104. PMC 1976238. PMID 17785424.
  38. ^ Xiang, X; Han, G; Winkelmann, DA; Zuo, W; Morris, NR. (2000). "Dynamics of cytoplasmic dynein in living cells and the effect of a mutation in the dynactin complex actin-related protein Arp1". Curr Biol. 10 (10): 603–6. doi:10.1016/S0960-9822(00)00488-7. PMID 10837229.
  39. ^ Bruno, KS; Tinsley, JH; Minke, PF; Plamann, M. (1996). "Genetic interactions among cytoplasmic dynein, dynactin, and nuclear distribution mutants of Neurospora crassa". Proc Natl Acad Sci U S A. 93 (10): 4775–80. doi:10.1073/pnas.93.10.4775. PMC 39355. PMID 8643479.
  40. ^ Salina, D; Bodoor, K; Eckley, DM; Schroer, TA; Rattner, JB; Burke, B (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.
  41. ^ Quintyne, NJ; Gill, SR; Eckley, DM; Cregoa, CL; Comptonb, DA; Schroer, TA (1999). "Dynactin Is Required for Microtubule Anchoring at Centrosomes". The Journal of Cell Biology. 147 (2): 321–334. doi:10.1083/jcb.147.2.321. PMC 2174233. PMID 10525538.
  42. ^ Quintyne, NJ; Schroer, TA (2002). "Distinct cell cycle–dependent roles for dynactin and dynein at centrosomes". The Journal of Cell Biology. 159 (2): 245–254. doi:10.1083/jcb.200203089. PMC 2173046. PMID 12391026.

Further reading

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