PhD project

PhD project

Cryo-EM and tomography studies of dynein-2 motor action and regulation

Supervisor: Katarina Toropova & Anthony Roberts

Dyneins are motor proteins in eukaryotic cells. Axonemal isoforms power flagellar beating, cytoplasmic dynein-1 transports cargoes in the cell interior, and dynein-2 – the focus of this project – is essential for the assembly and signalling functions of cilia and flagella. Mutations in dynein-2 cause a spectrum of severe human disorders spanning skeletal malformations to progressive loss of eyesight. Understanding the mechanism of dynein-2 and the basis for associated disease states has been challenging, as dyneins are large multi-protein complexes with molecular masses over 1 MDa. However, cryo-EM, tomography, and AI-assisted computational analyses have emerged as powerful tools to elucidate the action of these molecular machines in vitro and in cells. Here, you will team these techniques with protein biochemistry and fluorescence microscopy to address key questions in the functional cycle of dynein-2. This project would suit applicants with an interest in state-of-the-art structural biology and the fundamental mechanisms underlying human health.

Keywords:

  • Biochemistry, Biophysics, Cell Biology, Molecular Biology, Structural Biology

Publications:

  • Structure of the Dynein-2 Complex and its Assembly with Intraflagellar Transport Trains (2019) Toropova K, Zalyte R, Mukhopadhyay AG, Mladenov M, Carter AP, Roberts AJ. Nature Structural & Molecular Biology, 26(9):823-829. PMID: 31451806
  • Intraflagellar Transport Dynein is Autoinhibited by Trapping of its Mechanical and Track-binding Elements (2017) Toropova K, Mladenov M, Roberts AJ. Nature Structural & Molecular Biology, 24(5):461-468. PMID: 28394326
  • Structure and Tethering Mechanism of Dynein-2 Intermediate Chains in Intraflagellar Transport (2024) Mukhopadhyay AG, Toropova K, Daly L, Wells JN, Vuolo L, Mladenov M, Seda M, Jenkins D, Stephens DJ, Roberts AJ. EMBO J, 43(7):1257-1272. PMID: 38454149
  • DYNC2H1 hypomorphic or retina-predominant variants cause nonsyndromic retinal degeneration (2020) Vig A, Poulter JA, Ottaviani D, Tavares E, Toropova K… Roberts AJ, Heon E. Genet Med. 22(12):2041-2051. PMID: 32753734

Toropova lab

Discovering how molecular machines perform essential cellular functions using cryo-electron microscopy/tomography and live fluorescence imaging.

Roberts lab

Investigating how motor proteins generate movement and spatial organisation within living cells

Our PhD course

Doing a DPhil in Molecular Cell Biology in Health and Disease at the Dunn School is the best way to start your career.