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Dynamic Kinetochore Size Regulation Promotes Microtubule Capture And Chromosome Biorientation In Mitosis

Carlos Sacristan, Misbha Ahmad, Jenny Keller, Job Fermie, Vincent Groenewold, Eelco Tromer, Alexander Fish, Roberto Melero, Jose Maria Carazo, Judith Klumperman, Andrea Musacchio, Anastassis Perrakis, Geert JPL Kops

Preprint posted on March 12, 2018 https://www.biorxiv.org/content/early/2018/03/12/279398

and

Self-assembly of the RZZ complex into filaments drives kinetochore expansion in the absence of microtubule attachment

Cláudia Pereira, Rita M Reis, José B Gama, Dhanya K Cheerambathur, Ana X Carvalho, Reto Gassmann

Preprint posted on March 15, 2018 https://www.biorxiv.org/content/early/2018/03/15/282707

Catch me if you can: two preprints reveal the molecular interactions that allow outer kinetochores to expand and shrink dynamically in order to properly capture their microtubule targets in mitosis.

Selected by Gautam Dey

Context

The outer surfaces of kinetochores expand in early mitosis to form crescent-shaped structures thought to play an important role in forming proper chromosome-spindle attachments1. The crescent was named the “fibrous corona” for its distinctive appearance in early electron micrographs2. E.D. Salmon and colleagues demonstrated microtubule-dependent expansion and compaction in pioneering work3, but the fibrous corona’s complete molecular composition and proof of its predicted functional role have both proven somewhat elusive. Existing data on recruitment kinetics of various kinetochore components, along with structural predictions, hinted at starring roles for the ROD-ZW10-Zwilch (RZZ) complex and the dynein adaptor Spindly4.

 

Key findings

Sacristan et al., working in cell lines, first show that Spindly recruits dynein via three independent motifs to compact coronas. In vitro, purified RZZ complexes polymerise into filaments only in the presence of Spindly. In cells, Spindly uses its farnesyl (lipid) group to promote initial hydrophobic interactions with RZZ until phosphorylated and activated by the kinase Mps1. These conclusions are backed up by an impressive array of structural data. Expanded coronas that are incapable of shedding – as it is the case in Spindly mutants – form overly-stable “merotelic” attachments, in which chromosomes remain attached to microtubules from both poles.

Pereira, Reis et al. investigate the same RZZ-Spindly system in human cells, in vitro, and in C. elegans embryos. Chemically induced mitotic arrest, followed by forced mitotic exit, actually detaches the coronas from the centromeres, enabling the authors to assess their molecular composition – they find RZZ components, Spindly, CENP-E and the checkpoint proteins Mad1/2. Over-expression of only Rod produces expanded coronas, even when RZZ recruitment is impaired at an upstream step. Following up on this, the authors show that GFP-tagged Rod forms filaments in C. elegans embryos when it reaches a threshold concentration, but in a Spindly-independent fashion- an apparent discrepancy between humans and worms. Finally, the authors define a minimal RZZ complex capable of oligomerization in vitro.

 

From Pereira, Reis et al., Figure 1 (under CC-BY-NC-ND 4.0)

 

Why I chose these papers

It’s not every day that a field makes large strides in demystifying a cellular structure of likely fundamental importance. In addition, the intrinsic simplicity of the Spindly-RZZ system that emerges from these papers – despite the complexity of the spatial feedback loop it must execute – greatly appeals to me.

RZZ appears to share an evolutionary history with ancient nuclear pore and vesicle coat proteins5. The unusual combination of beta-propeller and alpha-solenoid domains that these proteins share played a fundamental role in the evolution of eukaryotes6 – raising the exciting possibility that RZZ will help us learn more about the evolution of the kinetochore7 and its role in early eukaryotic cell division.

 

What next?

New imaging and analytical tools have made it possible to track kinetochore dynamics in real-time with impressive resolution8. Applying these tools to RZZ and Spindly mutants will likely produce additional insights into the role of the fibrous corona in microtubule capture.

 

Of related recent interest in kinetochore biology

Not all kinetochores are the same! Check out these two preprints from the McClelland9 and Maiato10 labs on the differences in (mis)segregation behaviour between different chromosomes in a single cell.

 

References:

  1. Maiato, H., DeLuca, J., Salmon, E. D. & Earnshaw, W. C. The dynamic kinetochore-microtubule interface. J. Cell Sci. 117, 5461–77 (2004).
  2. McEwen, B. F., Arena, J. T., Frank, J. & Rieder, C. L. Structure of the colcemid-treated PtK1 kinetochore outer plate as determined by high voltage electron microscopic tomography. J. Cell Biol. 120, 301–12 (1993).
  3. Hoffman, D. B., Pearson, C. G., Yen, T. J., Howell, B. J. & Salmon, E. D. Microtubule-dependent changes in assembly of microtubule motor proteins and mitotic spindle checkpoint proteins at PtK1 kinetochores. Mol. Biol. Cell 12, 1995–2009 (2001).
  4. Mosalaganti, S. et al. Structure of the RZZ complex and molecular basis of its interaction with Spindly. J. Cell Biol. 216, 961–981 (2017).
  5. Civril, F. et al. Structural analysis of the RZZ complex reveals common ancestry with multisubunit vesicle tethering machinery. Structure 18, 616–26 (2010).
  6. Baum, D. A. A comparison of autogenous theories for the origin of eukaryotic cells. Am. J. Bot. 102, 1954–65 (2015).
  7. van Hooff, J. J., Tromer, E., van Wijk, L. M., Snel, B. & Kops, G. J. Evolutionary dynamics of the kinetochore network in eukaryotes as revealed by comparative genomics. EMBO Rep. 18, 1559–1571 (2017).
  8. Burroughs, N. J., Harry, E. F. & McAinsh, A. D. Super-resolution kinetochore tracking reveals the mechanisms of human sister kinetochore directional switching. Elife 4, (2015).
  9. Worrall, J. T. et al. Non-Random Mis-Segregation of Human Chromosomes. bioRxiv 278697 (2018). doi:10.1101/278697
  10. Drpic, D., Almeida, A., Aguiar, P. & Maiato, H. Chromosome (mis)segregation is biased by kinetochore size. bioRxiv 278572 (2018). doi:10.1101/278572

 

Tags: cell division, chromosome segregation, kinetochore

Posted on: 26th March 2018

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