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Structural Characterisation of Regulatory Interaction Networks Essential for Error-Free Chromosome Segregation

   School of Biological Sciences

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  Prof Jeyaprakash Arulanandam  No more applications being accepted  Self-Funded PhD Students Only

About the Project

*The difference between international and UK fee rate will be covered by the University of Edinburgh for successful candidates*

Supervisors: A. Jeyaprakash Arulanandam, Institute of Cell Biology, School of Biological Sciences, University of Edinburgh ([Email Address Removed]) and Yong Wang, College of Life Sciences, Zhejiang University ([Email Address Removed])

An MSc degree is not a requirement.

Project details

Cell division is a fundamental biological process essential for organismal growth and repair. Understanding the molecular mechanisms of accurate chromosome segregation is crucial as defects in this process often result in daughter cells with inappropriate chromosome number, a state called aneuploidy which is a hallmark of cancer. To ensure accurate cell division, the genetic information which is in the form chromosomes needs to be distributed equally to the newly formed daughter cells. Some of the key molecular processes essential for error-free chromosome segregation are: (i) physical attachment of chromosomes to the microtubule-based segregation machinery called the mitotic spindle and (ii) holding the sister chromatids together until all chromosomes (sister chromatid pairs) establish biorientation, where sister chromatids attach to microtubules emanating from opposite spindle poles. These processes are tightly regulated, both in space and time, by intricate protein interaction networks involving several multi-subunit protein assemblies such as the Chromosomal Passenger Complex, Cohesin, protein phosphatases, PP2A/B56. However, precise structural understanding of how these key players interact with and regulate each other remains unclear. One of the major challenges limiting the structural characterisation of these protein complexes is that the protein subunits constituting them are generally modular in nature with more than one globular domains connected by intrinsically unstructured linker regions, thus conferring flexibility and conformational heterogeneity. To overcome this, this project will employ an integrative structural modelling approach by combining experimental structural biology methods, such as X-ray crystallography, cryogenic electron microscopy (cryoEM), small angle X-ray scattering (SAXS), and cross-linking mass spectrometry (CLMS), with computational techniques including ab-initio structure prediction, molecular docking, multiscale modelling and molecular dynamics simulations. These structural analyses will allow us to perturb specific intermolecular interactions in vitro and in human cell lines (functional rescue assays) to evaluate the roles of specific intermolecular interactions in achieving accurate chromosome segregation. Overall, this integrative structure-function approach will provide novel mechanistic insights into the regulation of chromosome segregation.

PI Websites:

Jeyaprakash Arulanandam

 Yong Wang

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Funding Notes

The difference between international and UK fee rate will be covered by the University of Edinburgh for successful candidates. Successful candidates will be required to provide evidence of funding to cover the UK fee rate, plus living expenses of approximately £15k per year.


1. Thamkachy R*, Medina-Pritchard B*, Park SO*, Chiodi CG, Zou J, de la Torre-Barranco M, Shimanaka K, Abad MA, Páramo G, Feederle R, Ruksenaite E, Heun P, Davies OR, Rappsilber J, Schneidman-Duhovny D, Cho U-S and Jeyaprakash AA. Structural Basis for Mis18 Complex Assembly: Implications for Centromere Maintenance. bioRxiv (2021) DOI: 10.1101/2021.11.08.466737v1 (*equal contribution)
2. Medina-Pritchard B, Lazou V, Zou J, Byron O, Maria A Abad, Rappsilber J, Heun P and Jeyaprakash AA (2020). Structural Basis for Centromere Maintenance by Drosophila CENP-A chaperone Cal1. EMBO J. DOI: 10.15252/embj.2019103234
3. Abad MA, Ruppert JG*, Buzuk L*, Wear M, Zou J, Webb KM, Kelly DA, Voigt P, Rappsilber J, Earnshaw WC and Jeyaprakash AA (2019) Borealin-Nucleosome Interaction Secures Chromosome Association of the Chromosomal Passenger Complex. J Cell Biol. DOI: 10.1083/jcb.201905040 (*equal contribution)
4. Weinhaüpl K, Lindau C, Hessel A, Wang Y, Schütze C, Jores T, Kalbacher H, Rapaport D, Brennich M, Lindorff-Larsen K, Wiedemann N and Schanda P*. Structural Basis of Membrane Protein Chaperoning Through the Mitochondrial Intermembrane Space. Cell, 175, 1365-1379, (2018) DOI: 10.1016/j.cell.2018.10.039

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