Understanding a molecular architecture of the centriole / basal body

The aim of this PhD project is to determine the molecular assembly mechanism of a structure of the centriole / basal body by a combined approach of structure biology (cryo-EM and X-ray crystallography) and biochemistry in order to understand underlying mechanisms that cause ciliopathies and cancer.

Centrosomes play central roles in cell division by nucleating microtubules that equally divide duplicated chromosomes into two dividing cells. The failure of this process can cause loss of genomic information, which can result in cancer. In addition, centrosomes are essential for generating cilia because the core structure of the centrosome (called centriole) becomes the base of the cilium. The centriole is called the basal body at the cilium, but they are essentially the same structure. Cilia determine, for instance, positions of organs & the number of fingers in our body and are also essential for our vision and hearing. Cilia can be divided into two types: non-motile and motile cilia. Non-motile cilia (primary cilia) play a role in cell signalling. Since primary cilia are platforms for cancer signalling pathways such as the hedgehog signalling, their abnormal structures and generation can facilitate tumour growth. Motile cilia generate fluid flow (e.g. in airway to exclude mucus) and locomotion (e.g. in sperm). These cilia are conserved across eukaryotic species and can be found unicellular organisms such as green algae.

Since centrosomes and cilia are highly-ordered protein complexes, they must maintain correct architectures for their normal functions. Indeed, mutations within many centrosomal and ciliary genes result in their structural defects, and can cause ciliopathies, which are characterised by abnormal body development. Therefore, understanding how each protein contributes to build these organelles is important. However, we know little about exact contributions of most of centrosomal and ciliary proteins to their structures. To resolve this problem, my group currently focuses on determining the structure that is shared between the centrosome and cilium.

During the project, the successful candidate will use bacterial, insect and human cells for protein, production, purification and characterisation. Also, the student will have opportunities to learn how to use our state-of-art cryo-electron microscopes and analyse their data, and how to determine protein structures using X-ray crystallography. Most importantly, let’s enjoy doing science together!