Dynactin

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

Dynactin
Identifiers
Symbol Dynactin
Pfam PF12455
InterPro IPR022157
Dynamitin
Identifiers
Symbol Dynamitin
Pfam PF04912
InterPro IPR006996
Dynactin subunit p22
Identifiers
Symbol Dynactin_p22
Pfam PF07426
InterPro IPR009991
Dynactin p62 family
Identifiers
Symbol Dynactin_p62
Pfam PF05502
InterPro IPR008603

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 filament 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] Dynactin interacts with dynein directly by the binding of dynein intermediate chains with p150Glued.[6] DCTN2 (dynamitin) is also involved in anchoring microtubules to centrosomes and may play a role in synapse formation during brain development.[7] DCTN4 (p62) binds directly to the Arp1 subunit of dynactin.[8][9] Arp1 has been shown 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] 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][17][18]

Functions

Dynactin is often essential for dynein activity[1][19] and can be thought of as a "dynein receptor"[6] that modulates binding of dynein to cell organelles which are to be transported along microtubules.[20][21] Dynactin also enhances the processivity of cytoplasmic dynein[22] and kinesin-2 motors.[23] Dynactin is involved in various processes like chromosome alignment and spindle organization[24] in cell division.[25] Dynactin contributes to mitotic spindle pole focusing through its binding to nuclear mitotic apparatus protein (NuMA).[26][27] Dynactin also targets to the kinetochore through binding between DCTN2/dynamitin and zw10 and has a role in mitotic spindle checkpoint inactivation.[28][29] 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.[18] In addition, dynactin has been shown to play an essential role in maintaining nuclear position in Drosophila,[30] zebrafish[31] or in different fungi.[32][33] Dynein and dynactin concentrate on the nuclear envelope during the prophase and facilitate nuclear envelope breakdown via its DCTN4/p62 and Arp11 subunits.[16][34] Dynactin is also required for microtubule anchoring at centrosomes and centrosome integrity.[35] 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.[36] In addition to transport of various organelles in the cytoplasm, dynactin also links kinesin II to organelles.[2]

See also

References

  1. 1 2 3 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. 1 2 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.
  5. ↑ Eckley, DM; Gill, SR; Melkonian, K A.; Bingham, JB; Goodson, HV; Heuser, JE; Schroer, TA (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): 307–320. doi:10.1083/jcb.147.2.307. PMC 2174220. PMID 10525537.
  6. 1 2 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.
  7. ↑ Uetake Y, Terada Y, Matuliene J, Kuriyama R (May 2004). "Interaction of Cep135 with a p50 dynactin subunit in mammalian centrosomes". Cell Motil. Cytoskeleton 58 (1): 53–66. doi:10.1002/cm.10175. PMID 14983524.
  8. ↑ Karki S, Tokito MK, Holzbaur EL (February 2000). "A dynactin subunit with a highly conserved cysteine-rich motif interacts directly with Arp1". J. Biol. Chem. 275 (7): 4834–9. doi:10.1074/jbc.275.7.4834. PMID 10671518.
  9. ↑ Garces JA, Clark IB, Meyer DI, Vallee RB (1999). "Interaction of the p62 subunit of dynactin with Arp1 and the cortical actin cytoskeleton". Curr. Biol. 9 (24): 1497–500. doi:10.1016/S0960-9822(00)80122-0. PMID 10607597.
  10. ↑ Holleran, EA; Tokito, MK; Karki, S; Holzbaur, EL (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): 1815–1829. doi:10.1083/jcb.135.6.1815. PMC 2133946. PMID 8991093.
  11. ↑ Holleran, EA; Ligon, LA; Tokito, M; Stankewich, MC; Morrow, JS; Holzbaur, E.L. F. (2001). "βIII Spectrin Binds to the Arp1 Subunit of Dynactin". The Journal of Biological Chemistry 276 (39): 36598–36605. doi:10.1074/jbc.M104838200. PMID 11461920.
  12. ↑ Muresan, V; Stankewich, MC; Steffen, W; Morrow, JS; Holzbaur, EL; Schnapp, BJ (2001). "Dynactin-Dependent, Dynein-Driven Vesicle Transport in the Absence of Membrane Proteins". Molecular Cell 7 (1): 173–183. 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 (2007). "Activation of endosomal dynein motors by stepwise assembly of Rab7–RILP–p150Glued, ORP1L, and the receptor βlll spectrin". The Journal of Cell Biology 176 (4): 459–71. doi:10.1083/jcb.200606077. PMC 2063981. PMID 17283181.
  14. ↑ Salina, D; Bodoor, K; Eckley, DM; Schroer, TA; Rattner, JB; Burke, B (Jan 11, 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.
  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 (Copenhagen, Denmark) 9 (7): 1073–87. doi:10.1111/j.1600-0854.2008.00748.x. PMID 18410488.
  16. 1 2 3 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. PMID 22918948.
  17. ↑ 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. PMID 21708978.
  18. 1 2 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. PMID 23455152.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ Echeverri, CJ; Paschal, BM; Vaughan, KT; Vallee, RB (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): 617–633. doi:10.1083/jcb.132.4.617. PMC 2199864. PMID 8647893.
  25. ↑ 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.
  26. ↑ 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.
  27. ↑ 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.
  28. ↑ Howell, BJ; McEwen, BF; Canman, JC; Hoffman, DB; Farrar, EM; Rieder, CL; Salmon, ED. (2001). "Cytoplasmic dynein/dynactin drives kinetochore protein transport to the spindle poles and has a role in mitotic spindle checkpoint inactivation". J Cell Biol. 155 (7): 1159–72. doi:10.1083/jcb.200105093. PMC 2199338. PMID 11756470.
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ 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.
  34. ↑ 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.
  35. ↑ 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.
  36. ↑ 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

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

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