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Jeyaprakash Arulanandam


Maria Alba Abad-Fernandaz, Tanmay Gupta, Bethan Medina-Pritchard, Frances Spiller
Arulanandam (JP) lab

Structural Biology of Cell Division

Cell division is a fundamental molecular process of life that ensures accurate transfer of genetic information through generations. Errors in cell division often result in daughter cells with inappropriate chromosome numbers, a condition associated with cancers and birth defects. Key events that determine the accuracy of cell division include centromere specification, kinetochore assembly, physical attachment of kinetochores to spindle microtubules and successful completion of cytokinesis. These cellular events are regulated by a number of mitotic molecular machines (including the Chromosomal Passenger Complex (CPC), KMN (Knl1-Mis12-Ndc80) network, the Ska complex, Spindle Assembly Checkpoint and the Anaphase Promoting Complex) involving an extensive network of protein-protein interactions.

We are interested in understanding how specific protein-protein interactions involved in kinetochore assembly and function are translated into the regulation of cell division. Our current focus is on the protein complexes involved in centromere inheritance (Mis18 and Mis18 associated), the Chromosomal Passenger Complex (CPC), a key orchestrator of cell division and the Ska complex, an essential protein assembly required for efficient coupling of chromosomes to the spindle microtubules. The specific questions that we aim to address currently are i) What is molecular basis for the establishment and maintenance of CENP-A nucleosomes at centromeres? ii) What is the structural basis for the centromere and midbody association of the CPC? and iii) How does the Ska complex cooperate with the Ndc80 complex to stably couple chromosomes to spindle microtubules drive chromosome segregation? The structural and functional insights from these studies have the potential to provide new avenues of targeting specific protein-interactions to fight mitosis related human health disorders.

To achieve our goals, we combine structural, biochemical and cell biological methods. We use molecular biology and biochemical approaches to characterize protein interactions in vitro, X-ray crystallography, Small Angle X-ray Scattering (SAXS) and Electron Microscopy for structural analysis and a combination of in vitro and cell-based in vivo functional assays using structure-guided mutations for functional characterization. Our recent structural and biochemical work on Mis18, the central player involved in the regulation of centromere inheritance, in combination with yeast genetics (collaboration with Robin Allshire) elegantly showed that oligomerisation of Mis18 mediated via its ‘Yippee-like’ domain is crucial for its centromere localization and function (Subramanian & Medina-Pritchard et al., 2016).

Selected publications:

Subramanian, L., Medina-Pritchard, B., Barton, R., Spiller, F., Kulasegaran-Shylini, R., Radaviciute, G, Allshire, R. C and Jeyaprakash A. A. (2016) Centromere Localization and Function of Mis18 Requires ‘Yippee-Like’ Domain-Mediated Oligomerization. EMBO Reports. doi:10.15252/embr.201541520.

Papini, D., Langemeyer, L., Abad, M. A., Kerr, A., Samejima, I., Eyers, P. A., Jeyaprakash, A. A., Higgins, J. M. G., Barr, F. A. and Earnshaw, W. C. (2015). TD60 Links RalA GTPase Function to the CPC in Mitosis. Nat Commun 6, 7678. doi:10.1038/ncomms8678

Platani, M., Trinkle-Mulchay, L., Porter, M., Jeyaprakash, A. A and Earnshaw, W. C. (2015). Mio Depletion Links mTOR Regulation to Aurora A and Plk1 Activation at Mitotic Centrosomes. J Cell Biol. 210, 45-62.

Abad, M. A., Medina, B., Santamaria, A., Zou, J., Plasberg-Hill, C., Madhumalar, A., Jayachandran, U., Redli, P. M., Rappsilber, J., Nigg, E. A. and Jeyaprakash. A. A. (2014). Structural Basis for Microtubule Recognition by the Human Kinetochore Ska Complex. Nat Commun 5, 2964. doi:10.1038/ ncomms3964.

A. Domain organization of Mis18 proteins. B. Structural and functional characterization of S.pombe Mis18