Project title: Structural and molecular study of Astrin-PP1 interaction to uncover how cells monitor chromosome-microtubule attachment status and prevent chromosomal instability
Summary: When human cells undergo division, microtubules capture and segregate chromosomes into two equal sets. Chromosome-microtubule attachment is mediated by a large macromolecular structure - the Kinetochore (KT) - made of more than 100 proteins. Proper kinetochore assembly and function are essential for the accurate segregation of chromosomes. It has been shown that KTs attached to microtubule (MT) -ends, but not to walls, recruit a 4-member Astrin-SKAP complex, which stabilises KT-MT attachment. With the Pickersgill and Martin-Duran labs, the Draviam lab showed that Astrin's enrichment at the KT requires its interaction with PP1 phosphatase. Identifying why Astrin-PP1 interaction occurs only at KTs bound to MT-ends, and nowhere else in the cell, can reveal how cells monitor KT-MT attachment. Using a combination of molecular and cell biology and structural biology tools to define the structural and molecular basis for Astrin-PP1 interaction, I intend to uncover how cells monitor chromosome-microtubule attachment status and prevent chromosomal instability.