PhD project

Supervisor: Anthony Roberts

A major question in structural cell biology is how micrometer-scaled organelles are constructed and maintained. Cilia, also known as eukaryotic flagella, are multifunctional organelles that emanate from almost all cell types in the human body and many other eukaryotes. Nonmotile cilia serve as ‘signaling antennae’ in processes as diverse as morphogenesis, mechanosensation, and olfaction. Motile cilia beat with a wave-like motion essential for cellular propulsion and fluid flow. Severe congenital disorders are caused by defects in cilia, igniting interest in the mechanisms of ciliary assembly.

Underpinning the assembly and functions of cilia is a conserved motor-protein-driven process, called intraflagellar transport (IFT), which is the focus of our research [1-4]. Strikingly, this process involves multi-megadalton polymers, termed IFT “trains”, which move in a highly regulated fashion along the ciliary microtubules under the power of kinesin-2 and dynein-2 motors. Cargoes of IFT include ciliary building blocks (such as tubulin) and signaling molecules (such as G-protein coupled receptors). We use cryo-EM, cryo-ET, single-molecule fluorescence, and cell biology approaches to shed light on the molecular mechanisms of IFT. In this project, you will have the opportunity to focus on one of these techniques while being exposed to the full range, in order to address IFT mechanism. The project will be conducted in a friendly and supportive atmosphere with access to state-of-the-art equipment, including instruments for cryo-EM and FIB milling.

Publications:

• Hesketh SJ, Mukhopadhyay AG, Nakamura D, Toropova, K Roberts AJ (2022) IFT-A Structure Reveals Carriages for Membrane Protein Transport into Cilia. Cell, 185(26):4971-4985
• Webb S, Mukhopadhyay AG, Roberts AJ (2020) Intraflagellar Transport Trains and Motors: Insights from Structure. Seminars in Cell & Developmental Biology, 107:82-90
• Toropova K, Zalyte R, Mukhopadhyay AG, Mladenov M, Carter AP, Roberts AJ (2019) Structure of the Dynein-2 Complex and its Assembly with Intraflagellar Transport Trains. Nature Structural & Molecular Biology, 26(9):823-829
• Toropova K, Mladenov M, Roberts AJ (2017) Intraflagellar Transport Dynein is Autoinhibited by Trapping of its Mechanical and Track-binding Elements. Nature Structural & Molecular Biology, 24(5):461-468.