... understanding life in molecular detail

Dr Joe Cockburn

Structural biology of the cytoskeleton


Our interests lie in combining structural biology (principally X-ray crystallography), biophysical and cell biology approaches to obtain a unified understanding of cellular function. Broadly speaking, the research of my group aims to understands how cellular components are positioned inside the cell through interactions with the cytoskeleton.

Are you looking for a PhD place in structural biology for 2018? We currently have a PhD studentship through the BBSRC Doctoral Training Program to study structure and function of ciliary transition zone proteins, available for 2018 entry - go to https://www.findaphd.com/search/ProjectDetails.aspx?PJID=59606 for more details

Current major projects include:
  • How cellular cargo molecules recruit molecular motors and regulate the
  • Towards a molecular-level understanding of the ciliary transition zone
  • Molecular mechanisms of maternal effect factors

 

The main areas of current activity within my lab are described in more detail in the sections below.

 

How cellular cargo molecules recruit molecular motors and regulate their activities

The cytoplasm is a highly crowded environment containing tens of thousands of different protein species, mRNA molecules, ribosomes, vesicles and organelles. Cellular function is critically dependent on the correct localisation of these components in space and time.

The movement of cellular cargoes over long distances requires dedicated motor proteins (kinesins and cytoplasmic dynein) that use ATP hydrolysis to power movement along a dynamic network of tracks called microtubules. How these motors couple ATP hydrolysis to movement is now fairly well understood, and attention in the field is now turning towards the questions of how cellular cargoes recruit molecular motors and regulate their motility. The combined action of all the kinesin and dynein motors inside your body is very powerful – if all the kinesin motors in your cells were working at full tilt all the time, they would use up somewhere in the region of 8000 kcal of energy per day! Molecular motors must therefore be carefully regulated by their cargoes to ensure that they only consume energy then they are needed.

The main focus of our activity at present is on kinesin-1, which mediates the long-range transport of diverse cellular cargoes (proteins, mRNPs, vesicles, organelles and viruses). We use structural biology, biophysical and cell biology techniques to understand how kinesin-1 switches itself off when not in use, how cargo molecules bind to kinesin, and how this “switches on” kinesin-1.

Towards a molecular-level understanding of the ciliary transition zone (in collaboration with Prof. Colin Johnson at the Faculty of Medicine and Health, University of Leeds)

Cilia are the antennae of eukaryotic cells, sensing a wide variety of environmental signals (e.g light, molecules, proteins, and fluid flow). The cilium possesses a distinct protein and lipid composition relative to the rest of the cell. This is maintained by the transition zone, a large complex of over 20 proteins at the base of the cilium that controls the exchange of material between the cilium and the rest of the cell. Mutations in transition zone genes result in a range of autosomal recessive inherited disorders, such as nephronophthisis, Joubert Syndrome and Meckel-Gruber syndrome. Around 1% of the population are genetic carriers for these conditions.

We use a combination of structural and cell biology approaches to obtain a unified, molecular-level understanding of the function of transition zone proteins, and how mutations in transition zone genes cause diseases. This will aid in the development of gene therapies against these conditions. 

Molecular mechanisms of maternal effect factors (in collaboration with Prof. Eamonn Sheridan at the Faculty of Medicine and Health, University of Leeds)

The ovum is one of the largest cells in the human body. Following fertilisation by a sperm cell, the conceptus undergoes several rounds of cleavage to form a ball of undifferentiated cells called the morula. “Cleavage” refers to the fact that, in contrast to mitotic cell division in most other cell types, there is little synthesis of new cellular components (i.e. cell growth) beyond genome replication. Thus, the early stages of embryogenesis involve progressively dividing up the large, single-celled conceptus into a ball of progressively smaller daughter cells, each with its own copy of the nuclear genome.

The early stages of embryogenesis occur without de novo nuclear transcription, and therefore depend on maternally encoded proteins and RNA molecules (“maternal effect factors”) that were present in the ovum at fertilisation. The correct sorting of these maternal effect factors into daughter cells during cleavage of the conceptus is crucial for the progression of embryogenesis, and defects in this process caused by e.g. mutations in maternal effect genes can lead to infertility. We are investigating the structure and function of a number of maternal effect factors to understand their role in embryogenesis, how they are localised in the dividing embryo, and how mutations in maternal effect genes cause infertility.

Detailed research programme                  Close ▲
JJBC.jpg

Lecturer in X-ray Crystallography

DPhil (University of Oxford) 2000-2005
Postdoctoral Fellow (Pasteur Institute, Paris) 2005-2011
Postdoctoral Fellow (London Research Institute, CRUK) 2011-2014

Astbury building
School of Molecular and Cellular Biology
01133430758
j.j.b.cockburn@leeds.ac.uk

http://www.fbs.leeds.ac.uk/staff/profile.php?tag=Cockburn_J

Selected Publications

  1. S Shakeel, EC Dykeman, SJ White, A Ora, JJB Cockburn, SJ Butcher, PG Stockley, R Twarock. Genomic RNA folding mediates assembly of human parechovirus. Nature Commun (in press)

  2. Hesketh EL, Meshcheriakova Y, Dent KC, Saxena P, Thompson RF, Cockburn JJ, Lomonossoff GP, Ranson NA. Mechanisms of assembly and genome packaging in an RNA virus revealed by high-resolution cryo-EM. Nat Commun (2015)

  3. Cockburn JJ, Navarro ME, Staropoli I, Fretes N, Urvoas, A, Arenzana F, Bedouelle H, Rey FA. Mechanism of broad cross-neutralization of dengue virus by a monoclonal antibody. Structure 20(2):303-14 (2012)

  4. Cockburn JJ, Navarro Sanchez ME, Goncalvez AP, Zaitseva E, Stura EA, Kikuti CM, Duquerroy S, Dussart P, Chernomordik LV, Lai C-J, Rey FA. Structural insights into the neutralization mechanism of a higher primate antibody against dengue virus. EMBO J 31(3):767-79 (2012)