Kinetochores attached to microtubule-ends are stabilised by Astrin bound PP1 to ensure proper chromosome segregation.

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Gul, Parveen 
Islam, Asifa 
Martín-Durán, José M 
Pickersgill, Richard W 

Microtubules segregate chromosomes by attaching to macromolecular kinetochores. Only microtubule-end attached kinetochores can be pulled apart; how these end-on attachments are selectively recognised and stabilised is not known. Using the kinetochore and microtubule-associated protein, Astrin, as a molecular probe, we show that end-on attachments are rapidly stabilised by spatially-restricted delivery of PP1 near the C-terminus of Ndc80, a core kinetochore-microtubule linker. PP1 is delivered by the evolutionarily conserved tail of Astrin and this promotes Astrin's own enrichment creating a highly-responsive positive feedback, independent of biorientation. Abrogating Astrin:PP1-delivery disrupts attachment stability, which is not rescued by inhibiting Aurora-B, an attachment destabiliser, but is reversed by artificially tethering PP1 near the C-terminus of Ndc80. Constitutive Astrin:PP1-delivery disrupts chromosome congression and segregation, revealing a dynamic mechanism for stabilising attachments. Thus, Astrin-PP1 mediates a dynamic 'lock' that selectively and rapidly stabilises end-on attachments, independent of biorientation, and ensures proper chromosome segregation.


Funder: Islamic Development Bank; FundRef:

cell biology, chromosome, human, kinetochore, microtubule, mitosis, Alcian Blue, Aurora Kinase B, Chromosomal Proteins, Non-Histone, Chromosome Segregation, Cytoskeletal Proteins, HeLa Cells, Humans, Kinetochores, Metaphase, Microtubule-Associated Proteins, Microtubules, Molecular Docking Simulation, Phenazines, Phenothiazines, Protein Conformation, Protein Interaction Domains and Motifs, Receptors, Neuropeptide Y, Resorcinols
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eLife Sciences Publications, Ltd
Queen Mary University of London (SBC8DRA2)
Biotechnology and Biological Sciences Research Council (R01003X/1)
Cancer Research UK (C28598/A9787)
Medical Research Council (MR/K50127X/1)