Skip to main content
Log in

Protein Complex NDC80: Properties, Functions, and Possible Role in Pathophysiology of Cell Division

  • Review
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

Mitotic division maintains genetic identity of any multicellular organism throughout an entire lifetime. Each time a parent cell divides, chromosomes are equally distributed between the daughter cells due to the action of mitotic spindle. Mitotic spindle is formed by the microtubules that represent dynamic polymers of tubulin protein. Spindle microtubules are attached end-on to kinetochores – large multi-protein complexes on chromosomes. This review focuses on the four-subunit NDC80 complex, one of the most important kinetochore elements that plays a major role in the attachment of assembling/disassembling microtubule ends to the chromosomes. Here, we summarize published data on the structure, properties, and regulation of the NDC80 complex and discuss possible relationship between changes in the expression of genes coding for the NDC80 complex components, mitotic disorders, and oncogenesis with special emphasis on the diagnostic and therapeutic potential of NDC80.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.

Similar content being viewed by others

Abbreviations

a.a.:

amino acid residue

CH domain:

calponin homology domain

FRET:

Förster resonance energy transfer

REFERENCES

  1. Petry, S. (2016) Mechanisms of mitotic spindle assembly, Annu. Rev. Biochem., 85, 659-683, doi: 10.1146/annurev-biochem-060815-014528.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Miki-Noumura, T., and Mori, H. (1972) Polymerization of tubulin: the linear polymer and its side-by-side aggregates, J. Mechanochem. Cell. Motil., 1, 175-188, doi: 10.1038/331499a0.

    Article  CAS  PubMed  Google Scholar 

  3. Bergen, L. G., and Borisy, G. G. (1980) Head-to-tail polymerization of microtubules in vitro. Electron microscope analysis of seeded assembly, J. Cell Biol., 84, 141-150, doi: 10.1083/jcb.84.1.141.

    Article  CAS  PubMed  Google Scholar 

  4. Huitorel, P., and Kirschner, M. W. (1988) The polarity and stability of microtubule capture by the kinetochore, J. Cell Biol., 106, 151-159, doi: 10.1083/jcb.106.1.151.

    Article  CAS  PubMed  Google Scholar 

  5. Koshland, D. E., Mitchison, T. J., and Kirschner, M. W. (1988) Polewards chromosome movement driven by microtubule depolymerization in vitro, Nature, 331, 499-504.

    Article  CAS  Google Scholar 

  6. Mitchison, T. J., and Kirschner, M. W. (1985) Properties of the kinetochore in vitro. I. Microtubule nucleation and tubulin binding, J. Cell. Biol., 101, 755-765, doi: 10.1083/jcb.101.3.755.

    Article  CAS  PubMed  Google Scholar 

  7. McAinsh, A. D., Tytell, J. D., and Sorger, P. K. (2003) Structure, function, and regulation of budding yeast kinetochores, Annu. Rev. Cell Dev. Biol., 19, 519-539, doi: 10.1146/annurev.cellbio.19.111301.155607.

    Article  CAS  PubMed  Google Scholar 

  8. Westermann, S., Drubin, D. G., and Barnes, G. (2007) Structures and functions of yeast kinetochore complexes, Annu. Rev. Biochem., 76, 563-591, doi: 10.1146/annurev.biochem.76.052705.160607.

    Article  CAS  PubMed  Google Scholar 

  9. Cheeseman, I. M., and Desai, A. (2008) Molecular architecture of the kinetochore-microtubule interface, Nat. Rev. Mol. Cell Biol., 9, 33-46, doi: 10.1038/nrm2310.

    Article  CAS  PubMed  Google Scholar 

  10. Welburn, J. P. I., and Cheeseman, I. M. (2008) Toward a molecular structure of the eukaryotic kinetochore, Dev. Cell, 15, 645-655, doi: 10.1016/j.devcel.2008.10.011.

    Article  CAS  PubMed  Google Scholar 

  11. Cheeseman, I. M., Chappie, J. S., Wilson-Kubalek, E. M., and Desai, A. (2006) The conserved KMN network constitutes the core microtubule-binding site of the kinetochore, Cell, 127, 983-997, doi: 10.1016/j.cell.2006.09.039.

    Article  CAS  PubMed  Google Scholar 

  12. Janke, C., Ortiz, J., Lechner, J., Shevchenko, A., Shevchenko, A., Magiera, M. M., Schramm, C., and Schiebel, E. (2001) The budding yeast proteins Spc24p and Spc25p interact with Ndc80p and Nuf2p at the kinetochore and are important for kinetochore clustering and checkpoint control, EMBO J., 20, 777-791, doi: 10.1093/emboj/20.4.777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Joglekar, A. P., Bouck, D. C., Molk, J. N., Bloom, K. S., and Salmon, E. D. (2006) Molecular architecture of a kinetochore–microtubule attachment site, Nat. Cell Biol., 8, 581-585, doi: 10.1038/ncb1414.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Aravamudhan, P., Felzer-Kim, I., Gurunathan, K., and Joglekar, A. P. (2014) Assembling the protein architecture of the budding yeast kinetochore-microtubule attachment using FRET, Curr. Biol., 24, 1437-1446, doi: 10.1016/j.cub.2014.05.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Suzuki, A., Badger, B. L., and Salmon, E. D. (2015) A quantitative description of Ndc80 complex linkage to human kinetochores, Nat. Commun., 6, 8161, doi: 10.1038/ncomms9161.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Lawrimore, J., Bloom, K. S., and Salmon, E. D. (2011) Point centromeres contain more than a single centromere-specific Cse4 (CENP-A) nucleosome, J. Cell Biol., 195, 573-582, doi: 10.1083/jcb.201106036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bharadwaj, R., and Yu, H. (2004) The spindle checkpoint, aneuploidy, and cancer, Oncogene, 23, 2016-2027, doi: 10.1038/sj.onc.1207374.

    Article  CAS  PubMed  Google Scholar 

  18. Qu, Y., Li, J., Cai, Q., and Liu, B. (2014) Hec1/Ndc80 is overexpressed in human gastric cancer and regulates cell growth, J. Gastroenterol., 49, 408-418, doi: 10.1007/s00535-013-0809-y.

    Article  CAS  PubMed  Google Scholar 

  19. Hu, P., Chen, X., Sun, J., Bie, P., and Zhang, L.-D. (2015) siRNA-mediated knockdown against NUF2 suppresses pancreatic cancer proliferation in vitro and in vivo, Biosci. Rep., 35, doi: 10.1042/BSR20140124.

    Article  Google Scholar 

  20. Meng, Q.-C., Wang, H.-C., Song, Z.-L., Shan, Z.-Z., Yuan, Z., Zheng, Q., and Huang, X.-Y. (2015) Overexpression of NDC80 is correlated with prognosis of pancreatic cancer and regulates cell proliferation, Am. J. Cancer Res., 5, 1730-1740.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang, H., Gao, X., Lu, X., Wang, Y., Ma, C., Shi, Z., Zhu, F., He, B., Xu, C., and Sun, Y. (2015) The mitotic regulator Hec1 is a critical modulator of prostate cancer through the long non-coding RNA BX647187 in vitro, Biosci. Rep., 35, doi: 10.1042/BSR20150003.

    Google Scholar 

  22. Yan, X., Huang, L., Liu, L., Qin, H., and Song, Z. (2018) Nuclear division cycle 80 promotes malignant progression and predicts clinical outcome in colorectal cancer, Cancer Med., 7, 420-432, doi: 10.1002/cam4.1284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wei, R. R., Sorger, P. K., and Harrison, S. C. (2005) Molecular organization of the Ndc80 complex, an essential kinetochore component, Proc. Natl. Acad. Sci. USA, 102, 5363-5367, doi: 10.1073/pnas.0501168102.

    Article  CAS  PubMed  Google Scholar 

  24. DeLuca, J. G., Gall, W. E., Ciferri, C., Cimini, D., Musacchio, A., and Salmon, E. D. (2006) Kinetochore microtubule dynamics and attachment stability are regulated by Hec1, Cell, 127, 969-982, doi: 10.1016/j.cell.2006.09.047.

    Article  CAS  PubMed  Google Scholar 

  25. Wei, R. R., Al-Bassam, J., and Harrison, S. C. (2007) The Ndc80/HEC1 complex is a contact point for kinetochore–microtubule attachment, Nat. Struct. Mol. Biol., 14, 54-59, doi: 10.1038/nsmb1186.

    Article  CAS  PubMed  Google Scholar 

  26. Ciferri, C., Pasqualato, S., Screpanti, E., Varetti, G., Santaguida, S., Dos Reis, G., Maiolica, A., Polka, J., De Luca, J. G., and De Wulf, P. et al. (2008) Implications for kinetochore–microtubule attachment from the structure of an engineered Ndc80 complex, Cell, 133, 427-439, doi: 10.1016/j.cell.2008.03.020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sundin, L. J. R., Guimaraes, G. J., and Deluca, J. G. (2011) The NDC80 complex proteins Nuf2 and Hec1 make distinct contributions to kinetochore-microtubule attachment in mitosis, Mol. Biol. Cell, 22, 759-768, doi: 10.1091/mbc.E10-08-0671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. McCleland, M. L., Kallio, M. J., Barrett-Wilt, G. A., Kestner, C. A., Shabanowitz, J., Hunt, D. F., Gorbsky, G. J., and Stukenberg, P. T. (2004) The vertebrate Ndc80 complex contains Spc24 and Spc25 homologs, which are required to establish and maintain kinetochore-microtubule attachment, Curr. Biol., 14, 131-137, doi: 10.1016/j.cub.2003.12.058.

    Article  CAS  PubMed  Google Scholar 

  29. Malvezzi, F., Litos, G., Schleiffer, A., Heuck, A., Mechtler, K., Clausen, T., and Westermann, S. (2013) A structural basis for kinetochore recruitment of the Ndc80 complex via two distinct centromere receptors, EMBO J., 32, 409-423, doi: 10.1038/emboj.2012.356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wei, R. R., Schnell, J. R., Larsen, N. A., Sorger, P. K., Chou, J. J., and Harrison, S. C. (2006) Structure of a central component of the yeast kinetochore: the Spc24p/Spc25p globular domain, Structure, 14, 1003-1009, doi: 10.1016/j.str.2006.04.007.

    Article  CAS  PubMed  Google Scholar 

  31. Valverde, R., Ingram, J., and Harrison, S. C. (2016) Conserved tetramer junction in the kinetochore Ndc80 complex, Cell Rep., 17, 1915-1922, doi: 10.1016/j.celrep.2016.10.065.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mustyatsa, V. V., Boyakhchyan, A. V., Ataullakhanov, F. I., and Gudimchuk, N. B. (2017) EB-family proteins: functions and microtubule interaction mechanisms, Biochemistry (Moscow), 82, 791-802, doi: 10.1134/S0006297917070045.

    Article  CAS  Google Scholar 

  33. Wang, H.-W., Long, S., Ciferri, C., Westermann, S., Drubin, D., Barnes, G., and Nogales, E. (2008) Architecture and flexibility of the yeast Ndc80 kinetochore complex, J. Mol. Biol., 383, 894-903, doi: 10.1016/j.jmb.2008.08.077.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hsu, K.-S., and Toda, T. (2011) Ndc80 internal loop interacts with Dis1/TOG to ensure proper kinetochore-spindle attachment in fission yeast, Curr. Biol., 21, 214-220, doi: 10.1016/j.cub.2010.12.048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Varma, D., Chandrasekaran, S., Sundin, L. J. R., Reidy, K. T., Wan, X., Chasse, D. A. D., Nevis, K. R., DeLuca, J. G., Salmon, E. D., and Cook, J. G. (2012) Recruitment of the human Cdt1 replication licensing protein by the loop domain of Hec1 is required for stable kinetochore–microtubule attachment, Nat. Cell Biol., 14, 593-603, doi: 10.1038/ncb2489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhang, G., Kelstrup, C. D., Hu, X.-W., Kaas Hansen, M. J., Singleton, M. R., Olsen, J. V., and Nilsson, J. (2012) The Ndc80 internal loop is required for recruitment of the Ska complex to establish end-on microtubule attachment to kinetochores, J. Cell. Sci., 125, 3243-3253, doi: 10.1242/jcs.104208.

    Article  CAS  PubMed  Google Scholar 

  37. Tang, N. H., Takada, H., Hsu, K.-S., and Toda, T. (2013) The internal loop of fission yeast Ndc80 binds Alp7/TACC-Alp14/TOG and ensures proper chromosome attachment, Mol. Biol. Cell, 24, 1122-1133, doi: 10.1091/mbc.E12-11-0817.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Maure, J.-F., Komoto, S., Oku, Y., Mino, A., Pasqualato, S., Natsume, K., Clayton, L., Musacchio, A., and Tanaka, T. U. (2011) The Ndc80 loop region facilitates formation of kinetochore attachment to the dynamic microtubule plus end, Curr. Biol., 21, 207-213, doi: 10.1016/j.cub.2010.12.050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Joglekar, A. P., Bloom, K., and Salmon, E. D. (2009) In vivo protein architecture of the eukaryotic kinetochore with nanometer scale accuracy, Curr. Biol., 19, 694-699, doi: 10.1016/j.cub.2009.02.056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Scarborough, E. A., Davis, T. N., and Asbury, C. L. (2019) Tight bending of the Ndc80 complex provides intrinsic regulation of its binding to microtubules, Elife, 8, doi: 10.7554/eLife.44489.

    Article  Google Scholar 

  41. Tien, J. F., Umbreit, N. T., Zelter, A., Riffle, M., Hoopmann, M. R., Johnson, R. S., Fonslow, B. R., Yates, J. R., MacCoss, M. J., and Moritz, R. L. et al. (2014) Kinetochore biorientation in Saccharomyces cerevisiae requires a tightly folded conformation of the Ndc80 complex, Genetics, 198, 1483-1493, doi: 10.1534/genetics.114.167775.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Guimaraes, G. J., Dong, Y., McEwen, B. F., and Deluca, J. G. (2008) Kinetochore-microtubule attachment relies on the disordered N-terminal tail domain of Hec1, Curr. Biol., 18, 1778-1784, doi: 10.1016/j.cub.2008.08.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Miller, S. A., Johnson, M. L., and Stukenberg, P. T. (2008) Kinetochore attachments require an interaction between unstructured tails on microtubules and Ndc80(Hec1), Curr. Biol., 18, 1785-1791, doi: 10.1016/j.cub.2008.11.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Malik, R., Lenobel, R., Santamaria, A., Ries, A., Nigg, E. A., and Körner, R. (2009) Quantitative analysis of the human spindle phosphoproteome at distinct mitotic stages, J. Proteome Res., 8, 4553-4563, doi: 10.1021/pr9003773.

    Article  CAS  PubMed  Google Scholar 

  45. DeLuca, K. F., Meppelink, A., Broad, A. J., Mick, J. E., Peersen, O. B., Pektas, S., Lens, S. M. A., and DeLuca, J. G. (2018) Aurora A kinase phosphorylates Hec1 to regulate metaphase kinetochore–microtubule dynamics, J. Cell Biol., 217, 163-177, doi: 10.1083/jcb.201707160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. DeLuca, K. F., Lens, S. M. A., and DeLuca, J. G. (2011) Temporal changes in Hec1 phosphorylation control kinetochore–microtubule attachment stability during mitosis, J. Cell. Sci., 124, 622-634, doi: 10.1242/jcs.072629.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Biggins, S., Severin, F. F., Bhalla, N., Sassoon, I., Hyman, A. A., and Murray, A. W. (1999) The conserved protein kinase Ipl1 regulates microtubule binding to kinetochores in budding yeast, Genes Dev., 13, 532-544, doi: 10.1101/gad.13.5.532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Liu, D., Vleugel, M., Backer, C. B., Hori, T., Fukagawa, T., Cheeseman, I. M., and Lampson, M. A. (2010) Regulated targeting of protein phosphatase 1 to the outer kinetochore by KNL1 opposes Aurora B kinase, J. Cell Biol., 188, 809-820, doi: 10.1083/jcb.201001006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zaytsev, A. V., Sundin, L. J. R., DeLuca, K. F., Grishchuk, E. L., and DeLuca, J. G. (2014) Accurate phosphoregulation of kinetochore-microtubule affinity requires unconstrained molecular interactions, J. Cell. Biol., 206, 45-59, doi: 10.1083/jcb.201312107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yoo, T. Y., Choi, J.-M., Conway, W., Yu, C.-H., Pappu, R. V., and Needleman, D. J. (2018) Measuring NDC80 binding reveals the molecular basis of tension-dependent kinetochore-microtubule attachments, Elife, 7, doi: 10.7554/eLife.36392.

    Article  Google Scholar 

  51. Alushin, G. M., Ramey, V. H., Pasqualato, S., Ball, D. A., Grigorieff, N., Musacchio, A., and Nogales, E. (2010) The Ndc80 kinetochore complex forms oligomeric arrays along microtubules, Nature, 467, 805-810, doi: 10.1038/nature09423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Alushin, G. M., Musinipally, V., Matson, D., Tooley, J., Stukenberg, P. T., and Nogales, E. (2012) Multimodal microtubule binding by the Ndc80 kinetochore complex, Nat. Struct. Mol. Biol., 19, 1161-1167, doi: 10.1038/nsmb.2411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sarangapani, K. K., Akiyoshi, B., Duggan, N. M., Biggins, S., and Asbury, C. L. (2013) Phosphoregulation promotes release of kinetochores from dynamic microtubules via multiple mechanisms, Proc. Natl. Acad. Sci. USA, 110, 7282-7287, doi: 10.1073/pnas.1220700110.

    Article  PubMed  Google Scholar 

  54. Zaytsev, A. V., Mick, J. E., Maslennikov, E., Nikashin, B., DeLuca, J. G., and Grishchuk, E. L. (2015) Multisite phosphorylation of the NDC80 complex gradually tunes its microtubule-binding affinity, Mol. Biol. Cell, 26, 1829-1844, doi: 10.1091/mbc.E14-11-1539.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Petrovic, A., Pasqualato, S., Dube, P., Krenn, V., Santaguida, S., Cittaro, D., Monzani, S., Massimiliano, L., Keller, J., and Tarricone, A. et al. (2010) The MIS12 complex is a protein interaction hub for outer kinetochore assembly, J. Cell Biol., 190, 835-852, doi: 10.1083/jcb.201002070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Maskell, D. P., Hu, X.-W., and Singleton, M. R. (2010) Molecular architecture and assembly of the yeast kinetochore MIND complex, J. Cell Biol., 190, 823-834, doi: 10.1083/jcb.201002059.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Screpanti, E., De Antoni, A., Alushin, G. M., Petrovic, A., Melis, T., Nogales, E., and Musacchio, A. (2011) Direct binding of Cenp-C to the Mis12 complex joins the inner and outer kinetochore, Curr. Biol., 21, 391-398, doi: 10.1016/j.cub.2010.12.039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Gascoigne, K. E., Takeuchi, K., Suzuki, A., Hori, T., Fukagawa, T., and Cheeseman, I. M. (2011) Induced ectopic kinetochore assembly bypasses the requirement for CENP-A nucleosomes, Cell, 145, 410-422, doi: 10.1016/j.cell.2011.03.031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Yiap, B. C., Radhakrishnan, A. K., and Varma, N. R. (2008) DSN1 deletion is deleterious to the Saccharomyces cerevisiae while Dsn1p disrupts nuclear segregation process of Chinese hamster ovary cell, Afr. J. Biotech., 7, 2315-2320.

    CAS  Google Scholar 

  60. Kline, S. L., Cheeseman, I. M., Hori, T., Fukagawa, T., and Desai, A. (2006) The human Mis12 complex is required for kinetochore assembly and proper chromosome segregation, J. Cell Biol., 173, 9-17, doi: 10.1083/jcb.200509158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Schleiffer, A., Maier, M., Litos, G., Lampert, F., Hornung, P., Mechtler, K., and Westermann, S. (2012) CENP-T proteins are conserved centromere receptors of the Ndc80 complex, Nat. Cell Biol., 14, 604-613, doi: 10.1038/ncb2493.

    Article  CAS  PubMed  Google Scholar 

  62. Bock, L. J., Pagliuca, C., Kobayashi, N., Grove, R. A., Oku, Y., Shrestha, K., Alfieri, C., Golfieri, C., Oldani, A., and Dal Maschio, M. et al. (2012) Cnn1 inhibits the interactions between the KMN complexes of the yeast kinetochore, Nat. Cell Biol., 14, 614-624, doi: 10.1038/ncb2495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Palframan, W. J., Meehl, J. B., Jaspersen, S. L., Winey, M., and Murray, A. W. (2006) Anaphase inactivation of the spindle checkpoint, Science, 313, 680-684, doi: 10.1126/science.1127205.

    Article  CAS  PubMed  Google Scholar 

  64. Dhatchinamoorthy, K., Shivaraju, M., Lange, J. J., Rubinstein, B., Unruh, J. R., Slaughter, B. D., and Gerton, J. L. (2017) Structural plasticity of the living kinetochore, J. Cell Biol., 216, 3551-3570, doi: 10.1083/jcb.201703152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Lang, J., Barber, A., and Biggins, S. (2018) An assay for de novo kinetochore assembly reveals a key role for the CENP-T pathway in budding yeast, Elife, 7, doi: 10.7554/eLife.37819.

    Article  Google Scholar 

  66. Akiyoshi, B., Nelson, C. R., and Biggins, S. (2013) The aurora B kinase promotes inner and outer kinetochore interactions in budding yeast, Genetics, 194, 785-789, doi: 10.1534/genetics.113.150839.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Huis In’t Veld, P. J., Jeganathan, S., Petrovic, A., Singh, P., John, J., Krenn, V., Weissmann, F., Bange, T., and Musacchio, A. (2016) Molecular basis of outer kinetochore assembly on CENP-T, Elife, 5, doi: 10.7554/eLife.21007.

    Google Scholar 

  68. Caldas, G. V., and DeLuca, J. G. (2014) KNL1: bringing order to the kinetochore, Chromosoma, 123, 169-181, doi: 10.1007/s00412-013-0446-5.

    Article  CAS  PubMed  Google Scholar 

  69. Ghongane, P., Kapanidou, M., Asghar, A., Elowe, S., and Bolanos-Garcia, V. M. (2014) The dynamic protein Knl1-a kinetochore rendezvous, J. Cell. Sci., 127, 3415-3423, doi: 10.1242/jcs.149922.

    Article  CAS  PubMed  Google Scholar 

  70. Pagliuca, C., Draviam, V. M., Marco, E., Sorger, P. K., and De Wulf, P. (2009) Roles for the conserved spc105p/kre28p complex in kinetochore-microtubule binding and the spindle assembly checkpoint, PLoS One, 4, e7640, doi: 10.1371/journal.pone.0007640.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Espeut, J., Cheerambathur, D. K., Krenning, L., Oegema, K., and Desai, A. (2012) Microtubule binding by KNL-1 contributes to spindle checkpoint silencing at the kinetochore, J. Cell Biol., 196, 469-482, doi: 10.1083/jcb.201111107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kerres, A., Jakopec, V., and Fleig, U. (2007) The conserved Spc7 protein is required for spindle integrity and links kinetochore complexes in fission yeast, Mol. Biol. Cell, 18, 2441-2454, doi: 10.1091/mbc.e06-08-0738.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Jeyaprakash, A. A., Santamaria, A., Jayachandran, U., Chan, Y. W., Benda, C., Nigg, E. A., and Conti, E. (2012) Structural and functional organization of the Ska complex, a key component of the kinetochore–microtubule interface, Mol. Cell, 46, 274-286, doi: 10.1016/j.molcel.2012.03.005.

    Article  CAS  PubMed  Google Scholar 

  74. Helgeson, L. A., Zelter, A., Riffle, M., MacCoss, M. J., Asbury, C. L., and Davis, T. N. (2018) Human Ska complex and Ndc80 complex interact to form a load-bearing assembly that strengthens kinetochore-microtubule attachments, Proc. Natl. Acad. Sci. USA, 115, 2740-2745, doi: 10.1073/pnas.1718553115.

    Article  CAS  PubMed  Google Scholar 

  75. Wimbish, R., DeLuca, K. F., Mick, J. E., Himes, J., Sánchez, I. J., Jeyaprakash, A. A., and DeLuca, J. G. (2019) Coordination of NDC80 and Ska complexes at the kinetochore-microtubule interface in human cells, preprint, Cell Biol., doi: 10.1101/820530.

  76. Schmidt, J. C., Arthanari, H., Boeszoermenyi, A., Dashkevich, N. M., Wilson-Kubalek, E. M., Monnier, N., Markus, M., Oberer, M., Milligan, R. A., and Bathe, M. et al. (2012) The kinetochore-bound Ska1 complex tracks depolymerizing microtubules and binds to curved protofilaments, Dev. Cell, 23, 968-980, doi: 10.1016/j.devcel.2012.09.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Abad, M. A., Medina, B., Santamaria, A., Zou, J., Plasberg-Hill, C., Madhumalar, A., Jayachandran, U., Redli, P. M., Rappsilber, J., and Nigg, E. A. et al. (2014) Structural basis for microtubule recognition by the human kinetochore Ska complex, Nat. Commun., 5, 2964, doi: 10.1038/ncomms3964.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ramey, V. H., Wong, A., Fang, J., Howes, S., Barnes, G., and Nogales, E. (2011) Subunit organization in the Dam1 kinetochore complex and its ring around microtubules, Mol. Biol. Cell, 22, 4335-4342, doi: 10.1091/mbc.E11-07-0659.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Westermann, S., Avila-Sakar, A., Wang, H.-W., Niederstrasser, H., Wong, J., Drubin, D. G., Nogales, E., and Barnes, G. (2005) Formation of a dynamic kinetochore–microtubule interface through assembly of the Dam1 ring complex, Mol. Cell., 17, 277-290, doi: 10.1016/j.molcel.2004.12.019.

    Article  CAS  PubMed  Google Scholar 

  80. Miranda, J. J. L., De Wulf, P., Sorger, P. K., and Harrison, S. C. (2005) The yeast DASH complex forms closed rings on microtubules, Nat. Struct. Mol. Biol., 12, 138-143, doi: 10.1038/nsmb896.

    Article  CAS  PubMed  Google Scholar 

  81. Ng, C. T., Deng, L., Chen, C., Lim, H. H., Shi, J., Surana, U., and Gan, L. (2019) Electron cryotomography analysis of Dam1C/DASH at the kinetochore-spindle interface in situ, J. Cell Biol., 218, 455-473, doi: 10.1083/jcb.201809088.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Westermann, S., Wang, H.-W., Avila-Sakar, A., Drubin, D. G., Nogales, E., and Barnes, G. (2006) The Dam1 kinetochore ring complex moves processively on depolymerizing microtubule ends, Nature, 440, 565-569, doi: 10.1038/nature04409.

    Article  CAS  PubMed  Google Scholar 

  83. Grishchuk, E. L., Spiridonov, I. S., Volkov, V. A., Efremov, A., Westermann, S., Drubin, D., Barnes, G., Ataullakhanov, F. I., and McIntosh, J. R. (2008) Different assemblies of the DAM1 complex follow shortening microtubules by distinct mechanisms, Proc. Natl. Acad. Sci. USA, 105, 6918-6923, doi: 10.1073/pnas.0801811105.

    Article  PubMed  Google Scholar 

  84. Lampert, F., Hornung, P., and Westermann, S. (2010) The Dam1 complex confers microtubule plus end-tracking activity to the Ndc80 kinetochore complex, J. Cell Biol., 189, 641-649, doi: 10.1083/jcb.200912021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Gestaut, D. R., Graczyk, B., Cooper, J., Widlund, P. O., Zelter, A., Wordeman, L., Asbury, C. L., and Davis, T. N. (2008) Phosphoregulation and depolymerization-driven movement of the Dam1 complex do not require ring formation, Nat. Cell Biol., 10, 407-414, doi: 10.1038/ncb1702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Tien, J. F., Umbreit, N. T., Gestaut, D. R., Franck, A. D., Cooper, J., Wordeman, L., Gonen, T., Asbury, C. L., and Davis, T. N. (2010) Cooperation of the Dam1 and Ndc80 kinetochore complexes enhances microtubule coupling and is regulated by aurora B, J. Cell Biol., 189, 713-723, doi: 10.1083/jcb.200910142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Lampert, F., Mieck, C., Alushin, G. M., Nogales, E., and Westermann, S. (2013) Molecular requirements for the formation of a kinetochore-microtubule interface by Dam1 and Ndc80 complexes, J. Cell Biol., 200, 21-30, doi: 10.1083/jcb.201210091.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Volkov, V. A., Huis In’t Veld, P. J., Dogterom, M., and Musacchio, A. (2018) Multivalency of NDC80 in the outer kinetochore is essential to track shortening microtubules and generate forces, Elife, 7, doi: 10.7554/eLife.36764.

    Article  Google Scholar 

  89. Umbreit, N. T., Miller, M. P., Tien, J. F., Ortolá, J. C., Gui, L., Lee, K. K., Biggins, S., Asbury, C. L., and Davis, T. N. (2014) Kinetochores require oligomerization of Dam1 complex to maintain microtubule attachments against tension and promote biorientation, Nat. Commun., 5, 4951, doi: 10.1038/ncomms5951.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Kuriyan, J., and O’Donnell, M. (1993) Sliding clamps of DNA polymerases, J. Mol. Biol., 234, 915-925, doi: 10.1006/jmbi.1993.1644.

    Article  CAS  PubMed  Google Scholar 

  91. King, S. J., and Schroer, T. A. (2000) Dynactin increases the processivity of the cytoplasmic dynein motor, Nat. Cell Biol., 2, 20-24, doi: 10.1038/71338.

    Article  CAS  PubMed  Google Scholar 

  92. Kalantzaki, M., Kitamura, E., Zhang, T., Mino, A., Novák, B., and Tanaka, T. U. (2015) Kinetochore-microtubule error correction is driven by differentially regulated interaction modes, Nat. Cell Biol., 17, 421-433, doi: 10.1038/ncb3128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kim, J. O., Zelter, A., Umbreit, N. T., Bollozos, A., Riffle, M., Johnson, R., MacCoss, M. J., Asbury, C. L., and Davis, T. N. (2017) The Ndc80 complex bridges two Dam1 complex rings, Elife, 6, doi: 10.7554/eLife.21069.

    Google Scholar 

  94. Tang, N. H., and Toda, T. (2015) Alp7/TACC recruits kinesin-8-PP1 to the Ndc80 kinetochore protein for timely mitotic progression and chromosome movement, J. Cell. Sci., 128, 354-363, doi: 10.1242/jcs.160036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Miller, M. P., Asbury, C. L., and Biggins, S. (2016) A TOG protein confers tension sensitivity to kinetochore-microtubule attachments, Cell, 165, 1428-1439, doi: 10.1016/j.cell.2016.04.030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Agarwal, S., Smith, K. P., Zhou, Y., Suzuki, A., McKenney, R. J., and Varma, D. (2018) Cdt1 stabilizes kinetochore-microtubule attachments via an Aurora B kinase-dependent mechanism, J. Cell Biol., 217, 3446-3463, doi: 10.1083/jcb.201705127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Diaz-Rodríguez, E., Sotillo, R., Schvartzman, J.-M., and Benezra, R. (2008) Hec1 overexpression hyperactivates the mitotic checkpoint and induces tumor formation in vivo, Proc. Natl. Acad. Sci. USA, 105, 16719-16724, doi: 10.1073/pnas.0803504105.

    Article  PubMed  Google Scholar 

  98. Gurzov, E. N., and Izquierdo, M. (2006) RNA interference against Hec1 inhibits tumor growth in vivo, Gene Ther., 13, 1-7, doi: 10.1038/sj.gt.3302595.

    Article  CAS  PubMed  Google Scholar 

  99. Tang, N. H., and Toda, T. (2015) MAPping the Ndc80 loop in cancer: A possible link between Ndc80/Hec1 overproduction and cancer formation, Bioessays, 37, 248-256, doi: 10.1002/bies.201400175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Still, I. H., Vince, P., and Cowell, J. K. (1999) The third member of the transforming acidic coiled coil-containing gene family, TACC3, maps in 4p16, close to translocation breakpoints in multiple myeloma, and is upregulated in various cancer cell lines, Genomics, 58, 165-170, doi: 10.1006/geno.1999.5829.

    Article  CAS  PubMed  Google Scholar 

  101. Nagahara, M., Nishida, N., Iwatsuki, M., Ishimaru, S., Mimori, K., Tanaka, F., Nakagawa, T., Sato, T., Sugihara, K., and Hoon, D. S. et al. (2011) Kinesin 18A expression: clinical relevance to colorectal cancer progression, Int. J. Cancer, 129, 2543-2552, doi: 10.1002/ijc.25916.

    Article  CAS  PubMed  Google Scholar 

  102. Karavias, D., Maroulis, I., Papadaki, H., Gogos, C., Kakkos, S., Karavias, D., and Bravou, V. (2016) Overexpression of CDT1 is a predictor of poor survival in patients with hepatocellular carcinoma, J. Gastrointest. Surg., 20, 568-579, doi: 10.1007/s11605-015-2960-7.

    Article  PubMed  Google Scholar 

  103. Ling, Y., Zhang, X., Bai, Y., Li, P., Wei, C., Song, T., Zheng, Z., Guan, K., Zhang, Y., and Zhang, B. et al. (2014) Overexpression of Mps1 in colon cancer cells attenuates the spindle assembly checkpoint and increases aneuploidy, Biochem. Biophys. Res. Commun., 450, 1690-1695, doi: 10.1016/j.bbrc.2014.07.071.

    Article  CAS  PubMed  Google Scholar 

  104. Sotillo, R., Hernando, E., Díaz-Rodríguez, E., Teruya-Feldstein, J., Cordón-Cardo, C., Lowe, S. W., and Benezra, R. (2007) Mad2 overexpression promotes aneuploidy and tumorigenesis in mice, Cancer Cell, 11, 9-23, doi: 10.1016/j.ccr.2006.10.019.

    Article  CAS  PubMed  Google Scholar 

  105. Screpanti, E., Santaguida, S., Nguyen, T., Silvestri, R., Gussio, R., Musacchio, A., Hamel, E., and De Wulf, P. (2010) A screen for kinetochore–microtubule interaction inhibitors identifies novel antitubulin compounds, PLoS One, 5, e11603, doi: 10.1371/journal.pone.0011603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Wu, G., Qiu, X.-L., Zhou, L., Zhu, J., Chamberlin, R., Lau, J., Chen, P.-L., and Lee, W.-H. (2008) Small molecule targeting the Hec1/Nek2 mitotic pathway suppresses tumor cell growth in culture and in animal, Cancer Res., 68, 8393-8399, doi: 10.1158/0008-5472.CAN-08-1915.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Huang, L. Y. L., Lee, Y.-S., Huang, J.-J., Chang, C., Chang, J.-M., Chuang, S.-H., Kao, K.-J., Tsai, Y.-J., Tsai, P.-Y., and Liu, C.-W. et al. (2014) Characterization of the biological activity of a potent small molecule Hec1 inhibitor TAI-1, J. Exp. Clin. Cancer Res., 33, 6, doi: 10.1186/1756-9966-33-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Huang, L. Y. L., Chang, C.-C., Lee, Y.-S., Chang, J.-M., Huang, J.-J., Chuang, S.-H., Kao, K.-J., Lau, G. M. G., Tsai, P.-Y., and Liu, C.-W. et al. (2014) Activity of a novel Hec1-targeted anticancer compound against breast cancer cell lines in vitro and in vivo, Mol. Cancer Ther., 13, 1419-1430, doi: 10.1158/1535-7163.MCT-13-0700.

    Article  CAS  PubMed  Google Scholar 

  109. Hu, C.-M., Zhu, J., Guo, X. E., Chen, W., Qiu, X.-L., Ngo, B., Chien, R., Wang, Y. V., Tsai, C. Y., and Wu, G. et al. (2015) Novel small molecules disrupting Hec1/Nek2 interaction ablate tumor progression by triggering Nek2 degradation through a death-trap mechanism, Oncogene, 34, 1220-1230, doi: 10.1038/onc.2014.67.

    Article  CAS  PubMed  Google Scholar 

  110. Carozzi, V. A., Canta, A., and Chiorazzi, A. (2015) Chemotherapy-induced peripheral neuropathy: what do we know about mechanisms? Neurosci. Lett., 596, 90-107, doi: 10.1016/j. neulet. 2014.10.014.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by the Russian Science Foundation (project No. 17-74-20152).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to N. B. Gudimchuk.

Ethics declarations

This article does not contain any studies involving human participants or animals performed by any of the authors. The authors declare that they have no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ustinov, N., Korshunova, A. & Gudimchuk, N. Protein Complex NDC80: Properties, Functions, and Possible Role in Pathophysiology of Cell Division. Biochemistry Moscow 85, 448–462 (2020). https://doi.org/10.1134/S0006297920040057

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297920040057

Keywords

Navigation