The molecular basis of ciliopathy causing mutations in the ciliary assembly machinery
Nevin Korath Zacharia (ESR1)
Nevin completed his Bachelor’s and Master’s education from Indian Institute of Science Education and Research (IISER) Pune, in India where he was pursuing an Integrated BS-MS dual degree program in Biological Sciences. During his Master’s studies, he got the opportunity to work on a year-long research project in conducting structure-function studies on Bacterial restriction enzymes. His work in this project got him interested in the field of protein structure and motivated him to pursue a PhD project in this field. He joined the SCilS network as a PhD researcher in October 2020 to work on the structure and function of the Intraflagellar transport proteins that are necessary for cilium formation and function.
Nevin successfully defended his PhD thesis in February 2024. His PhD thesis was titled “Structural and biochemical characterization of the Intraflagellar transport protein IFT172 uncovers an atypical U-box E3 ubiquitin ligase domain”. This PhD work was conducted under the supervision of Prof. Esben Lorentzen in the Department of Molecular Biology and Genetics at Aarhus University, Denmark.
After completing his PhD, he began a new position as a Development Scientist at Novo Nordisk in Denmark.
What does Nevin say about our program?
I had a wonderful experience as an ESR in the SCilS consortium. Being part of this network allowed me to collaborate alongside researchers with diverse expertise and perspectives. The research exchanges provided opportunities to work in various laboratories, giving me exposure to new techniques and methodologies that were invaluable to my PhD project. Finally, the opportunity to be on the PhD journey alongside 13 other ESR fellows was an enriching and memorable experience for me.
Abstract
The formation and maintenance of cilia is dependent on an intracellular transport system (Intraflagellar Transport or IFT), mediated by 22 IFT subunits and the molecular motors Kinesin and Dynein. IFT172 is an IFT complex subunit and recent clinical studies have identified several human ciliopathy patients with mutations in the IFT172 subunit. This research project will be aimed at investigating the function of the IFT172 subunit in cilia so as to arrive at a molecular basis for these ciliopathies. X-ray crystallography will be utilized to investigate the structure of independent functional domains of the subunit. Utilising the insights obtained from the structure, various in vitro biochemical assays and in vivo assays in ciliated human cell lines will be designed to characterize the potential function of the IFT172 subunit. Furthermore, the activity and structure of IFT172 variants carrying patient mutations will be investigated to determine how these mutations affect IFT172 function in cilia and lead to ciliopathies.
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Layman abstract
Structural and functional studies on the intraflagellar transport complex
Cilia are hair-like growths present on most cells that allows the cell to sense its external environment. The Formation of cilia requires a protein called the intraflagellar transport (IFT) complex that transports substances from the cell body to the cilia. IFT is essential for proper cilia function and mutations in IFT genes have been shown to result in several human diseases. My work focuses on studying how the three-dimensional structure of the IFT complex proteins affects its function in intraflagellar transport and how mutations affect its structure and leading to the development of diseases.