One of the largest protein structures in the cell is the synaptonemal complex (SC), which synapses together homologous chromosomes to facilitate their recombination during meiosis. As such, the SC is essential for fertility, and its defects lead to human infertility, recurrent miscarriage, and aneuploidy. The zipper-like structure of the SC is up to 25 micrometres in length, and forms through self-assembly of its eight coiled-coil protein constituents. This occurs by formation of three distinct architectural self-assembled units. Firstly, SYCP3 assembles into a paracrystalline array that loops and compacts chromatin within linear chromosome axes (Syrjanen et al 2014). Then, SYCP1 forms a recursive lattice-like array that binds together homologous chromosome with a 100 nm separation (Dunce et al 2018). Finally, SYCE2-TEX12 undergoes hierarchical assembly from a 2:2 complex through a 4:4 structure into micrometre-length fibres, which resemble intermediate filaments, and provide structural support for SC growth along the chromosome length (Dunce et al 2021).
This PhD project aims to uncover the physics of how the SC’s coiled-coil protein components self-assemble into its principal architectural units. We will use computational methods to design mutants and re-engineer proteins with altered self-assembly characteristics, such as rigidity, repeating units, width and length, to probe the biology and widen the range of SC-related biomaterials. We will test these biochemically, determining structures and assembly dynamics by biophysics and structural biology. Our findings will lead to experimentally-determined structures of large-scale macromolecular assemblies and mathematical models of dynamic coiled-coil protein self-assembly. The outcomes of this integrated experimental and computational project are wide-reaching. Firstly, high-resolution structures of engineered protein assemblies will provide unprecedented understanding of the molecular structure of the SC, overcoming the current technical limitations of studying native SC proteins. These biological findings will be tested through the generation of mouse mutants by our collaborators at the MRC Human Genetics Unit (https://www.ed.ac.uk/mrc-human-genetics-unit). Secondly, it will establish a physical basis for supramolecular self-assembly of coiled-coil proteins that will be applicable to a wide range of biological systems. Finally, it will determine how we can manipulate the unique biochemical structures formed by SC proteins for research and for use as biomaterials.
This project will involve a wide range of biochemical, biophysical, structural biology, computational and theoretical modelling methods. The laboratory-based methods include recombinant protein expression and purification, light and X-ray scattering, X-ray crystallography, cryo-EM and cryo-ET, which will include data collection at the Diamond Light Source synchrotron facility (www.diamond.ac.uk). Computational and theoretical methods include AI-based structural modelling, molecular dynamics, and building and simulating mathematical models of bio-assemblies, which will be performed in collaboration with the Institute for Condensed Matter and Complex Systems (https://www.ph.ed.ac.uk/icmcs).
This PhD provides an excellent opportunity for a student with a biochemical/structural biology, computational or physics background to engage in cutting-edge research into the physics of life.
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