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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
doi: https://doi.org/10.1101/282707
Cláudia Pereira
1Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135 Porto, Portugal
2Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, 4200-135 Porto, Portugal
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Rita M. Reis
1Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135 Porto, Portugal
2Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, 4200-135 Porto, Portugal
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José B. Gama
1Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135 Porto, Portugal
2Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, 4200-135 Porto, Portugal
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Dhanya K. Cheerambathur
3Ludwig Institute for Cancer Research/Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA
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Ana X. Carvalho
1Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135 Porto, Portugal
2Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, 4200-135 Porto, Portugal
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Reto Gassmann
1Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135 Porto, Portugal
2Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, 4200-135 Porto, Portugal
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  • For correspondence: rgassmann@ibmc.up.pt
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SUMMARY

The kinetochore is a dynamic multi-protein assembly that forms on each sister chromatid and interacts with microtubules of the mitotic spindle to drive chromosome segregation. In animals, kinetochores without attached microtubules expand their outermost layer into crescent and ring shapes to promote microtubule capture and spindle assembly checkpoint (SAC) signalling. Kinetochore expansion is an example of protein co-polymerization, but the mechanism is not understood. Here, we present evidence that kinetochore expansion is driven by oligomerization of the Rod-Zw10-Zwilch (RZZ) complex, an outer kinetochore component that recruits the motor dynein and the SAC proteins Mad1-Mad2. Depletion of ROD in human cells suppresses kinetochore expansion, as does depletion of Spindly, the adaptor that connects RZZ to dynein, while dynein itself is dispensable. Expansion is also suppressed by mutating ZWILCH residues implicated in Spindly binding. Conversely, supplying cells with excess ROD facilitates kinetochore expansion under otherwise prohibitive conditions. Using the C. elegans early embryo, we demonstrate that ROD-1 has a concentration-dependent propensity for oligomerizing into µm-scale filaments, and we identify the ROD-1 β-propeller as a key regulator of self-assembly. Finally, we show that a minimal ROD-1-Zw10 complex efficiently oligomerizes into filaments in vitro. Our results suggest that RZZ’s capacity for oligomerization is harnessed by kinetochores to assemble the expanded outermost domain, in which RZZ filaments serve as recruitment platforms for SAC components and microtubule-binding proteins. Thus, we propose that RZZ self-assembly into filaments underlies the adaptive change in kinetochore size that contributes to chromosome segregation fidelity.

Footnotes

  • ↵$ : Equal contribution

  • Address: Instituto de Investigação e Inovação em Saúde (I3S) Room 201S2, Rua Alfredo Allen, 208 4200-135 Porto Portugal, Tel: +351 220408800, Lab x6124, Office x6125

  • Abbreviations used in this paper: NEBD, nuclear envelope breakdown; RZZ, Rod-Zw10-Zwilch complex; SAC, spindle assembly checkpoint

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 15, 2018.
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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
bioRxiv 282707; doi: https://doi.org/10.1101/282707
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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
bioRxiv 282707; doi: https://doi.org/10.1101/282707

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