KIF2C condensation concentrates PLK1 and phosphorylated BRCA2 on kinetochore microtubules in mitosis
Anastasiia Skobelkina1, Manon Julien1, Sylvain Jeannin1
1Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Saclay, 91190 Gif-sur-Yvette, France.
Abstract:
During mitosis, the microtubule depolymerase KIF2C, the tumor suppressor BRCA2, and the kinase PLK1 contribute to the control of kinetochore-microtubule attachments. Both KIF2C and BRCA2 are phosphorylated by PLK1, and BRCA2 phosphorylated at T207 (BRCA2-pT207) serves as a docking site for PLK1. Reducing this interaction results in unstable microtubule-kinetochore attachments. Here we identified that KIF2C also directly interacts with BRCA2-pT207. Indeed, the N-terminal domain of KIF2C adopts a Tudor/PWWP/MBT fold that unexpectedly binds to phosphorylated motifs. Using an optogenetic platform, we found that KIF2C forms membrane-less organelles that assemble through interactions mediated by this phospho-binding domain. KIF2C condensation does not depend on BRCA2-pT207 but requires active Aurora B and PLK1 kinases. Moreover, it concentrates PLK1 and BRCA2-pT207 in an Aurora B-dependent manner. Finally, KIF2C depolymerase activity promotes the formation of KIF2C condensates, but strikingly, KIF2C condensates exclude tubulin: they are located on microtubules, especially at their extremities. Altogether, our results suggest that, during the attachment of kinetochores to microtubules, the assembly of KIF2C condensates amplifies PLK1 and KIF2C catalytic activities and spatially concentrates BRCA2-pT207 at the extremities of microtubules. We propose that this novel and highly regulated mechanism contributes to the control of microtubule-kinetochore attachments, chromosome alignment, and stability.
Insights
KIF2C forms novel condensates that enhance PLK1 and KIF2C activity, concentrating BRCA2-pT207 at microtubule ends to control chromosome attachments during mitosis.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- KIF2C, BRCA2, and PLK1 are crucial for kinetochore-microtubule attachments during mitosis.
- PLK1 phosphorylates KIF2C and BRCA2, with BRCA2-pT207 acting as a PLK1 docking site, essential for stable attachments.
Purpose of the Study:
- To investigate the interaction between KIF2C and BRCA2-pT207.
- To elucidate the mechanism of KIF2C condensate formation and its role in regulating microtubule-kinetochore attachments.
Main Methods:
- Utilized an optogenetic platform to study KIF2C condensate assembly.
- Investigated protein-protein interactions using phospho-binding domain analysis.
- Assessed the role of Aurora B and PLK1 kinases in KIF2C condensation.
- Examined KIF2C depolymerase activity and its effect on condensate localization.
Main Results:
- Identified a direct interaction between KIF2C and BRCA2-pT207 via KIF2C's N-terminal phospho-binding domain.
- Demonstrated that KIF2C forms membrane-less organelles (condensates) dependent on Aurora B and PLK1, but not BRCA2-pT207.
- Showed that KIF2C condensates concentrate PLK1 and BRCA2-pT207 in an Aurora B-dependent manner.
- Found that KIF2C condensates are located on microtubules, excluding tubulin, and are promoted by KIF2C depolymerase activity.
Conclusions:
- KIF2C condensate assembly amplifies PLK1 and KIF2C catalytic activities.
- These condensates spatially concentrate BRCA2-pT207 at microtubule extremities.
- This mechanism contributes to the regulation of microtubule-kinetochore attachments, chromosome alignment, and stability during mitosis.
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