DCTN6

DCTN6 is the gene of p27 subunit of the dynactin complex, which is the essential component for microtubule-based cytoplasmic dynein motor activity in transport of variety of intracellular cargoes and organelle. It is first identified and cloned as a subunit of the "pointed-end complex" of dynactin through biochemical purification.[1] Dynactin p27 forms a hetero-dimer with the other dynactin pointed-end complex subunit p25/DCTN5 in 1:1 ratio, and it is essential for p25 stability since they are co-knockdown by p27 RNAi. However, both p27 and p25 are not required for 19S dynactin complex integrity verified by velocity sedimentation.[2][3] p27/DCTN6 and other dynactin pointed-end complex subunits (Arp11/Actr10, p62/DCTN4, and p25/DCTN5) have been suggested to be involved in dynactin binding to specific intracellular cargoes.[4] Co-depletion of dynactin p27 and p25 by p27 RNAi affects dynactin binding to endomembrane, and early and recycling endosome movements are impaired, suggesting that p27/p25 form a selective endomembrane cargo-targeting module.[5]

In mitosis, unlike dynactin or dynein perturbation that causes mitotic spindle disarrangement and mitotic arrest, dynactin p27/p25 depletion are does not affect mitotic spindle formation, pole focusing or dynein/dynactin targeting to kinetochores. However, dynactin p27/p25 are required for normal chromosome alignment, kinetochore-microtubule interaction, and proper timing of anaphase onset. Dynactin p27 C-terminal T186 residue is phosphorylated by cyclin-dependent kinase 1 (Cdk1) in mitosis and helps target polo-like kinase 1 (Plk1) to kinetochores during prometaphase. This activity facilitates phosphorylation of important downstream kinetochore targets (such as tension-sensing 3F3/2 phospho-epitope) of Plk1, which is important for recruitment of spindle assembly checkpoint proteins such as Mad1 and proper kinetochore-microtubule attachment. X-ray crystal structure revealed that dynactin p27 forms an unusual left handed β-helix (LβH) domain, and its phosphorylation site T186 is in C-terminal disordered segment.[6]

References

  1. ↑ Eckley, DM; Gill, SR; Melkonian, KA; Bingham, JB; Goodson, HV; Heuser, JE; Schroer, TA (Oct 18, 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.
  2. ↑ Eckley, DM; Gill, SR; Melkonian, KA; Bingham, JB; Goodson, HV; Heuser, JE; Schroer, TA (Oct 18, 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.
  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.
  4. ↑ Schroer, TA (2004). "Dynactin.". Annual Review of Cell and Developmental Biology 20: 759–79. doi:10.1146/annurev.cellbio.20.012103.094623. PMID 15473859.
  5. ↑ 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.
  6. ↑ 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.
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