The molecular interactions allowing Mps1 to safeguard cell division

Samenvatting

During cell division, all chromosomes have to line up and get attached through their kinetochores to spindle microtubules. Errors in this process lead to developmental defects and cancer. The spindle assembly checkpoint (SAC) is a signalling mechanism that inhibits the progress of cell division until all chromosomes are bipolarly attached. But how does the SAC 'sense' whether chromosomes are attached to spindle microtubules or not?

Our preliminary evidence shows that the predominant SAC kinase, Mps1, competes with microtubules for binding to the Ndc80 complex (Ndc80C) on kinetochores. This provides a simple model for attachment sensing by the SAC: Mps1 binds to Hec1 only when its binding site is unoccupied by a microtubule. When a chromosome establishes and maintains stable interactions with microtubules, Mps1 is excluded and this event silences SAC signalling.

Elucidating the exact mode of interaction of Mps1 and Ndc80C and its regulation is therefore crucial in understanding error-free chromosome segregation, and this will be the goal of my studies. In the past year, I found that the phosphorylation state of N-terminal region of Mps1, the NTE-TPR module, modulates the complex formation between Mps1 and Ndc80C.

I will first analyse the high affinity and low affinity states of the NTE-TPR module by mass spectrometry, to understand which sites are primarily responsible for modulating its affinity with the Ndc80C. Next I want to understand the structure of these high and low affinity states of NTE-TPR. Finally, I will build the structural model of Mps1-Ndc80C complex by integrating biophysical data from various methodologies.

This study will illuminate the molecular mechanisms of cell division, but will also lead to understand how we can use this protein interactions as a novel drug target for cancer therapy.

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Projectnummer

722.015.008

Hoofdaanvrager

Dr. Y. Hiruma

Verbonden aan

Nederlands Kanker Instituut, Antoni van Leeuwenhoek Ziekenhuis, Biochemie B8

Uitvoerders

Dr. Y. Hiruma

Looptijd

01/10/2015 tot 30/09/2018