I studied Physics Engineering at Politecnico di Milano (Milano, Italy), where I earned a bachelor’s degree followed by a master’s degree. Both of them consisted mainly of solid state physics classes, with a particular focus on semiconductors (for electronics and photonics application) and magnetic nanostructures. My first experience in research was at the European Synchrotron Radiation Facility (Grenoble, France), where I spent 10 months working as a trainee for my master thesis project.
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Brief project description:
Introduction & Background
In 2003, the Ras of complex proteins (ROCO) proteins were identified as large multi-domain proteins and have been the subject of intense scrutiny, resulting from their association with a number of human diseases including Parkinson’s and cancer. ROCO proteins are unique in the human proteome as they are the only proteins to pair a GTPase domain with a kinase domain in the same open reading frame. As both are key enzymatic domains involved in cell signalling, it is likely that ROCO proteins act as cellular signal transduction hubs. To date, much of the research of the human ROCO proteins has been limited to LRRK2, as a key player in Parkinson’s disease, but a general understanding is still lacking. However, ROCO proteins are being actively investigated as potential therapeutic targets for human disease – emphasising the importance of generating structural data for this family of proteins.
Outline of Project
The aim of this project is to understand how the ROCO proteins integrate cell-signalling pathways at a structural level, using human ROCO proteins as models. To achieve this, a multi-construct multi-host strategy will be adopted to produce full-length and combinations of protein domains prior to structural analysis by crystallography and/or cryo-EM analysis. Analysis of structural dynamics will be supported by a range of techniques including Synchrotron Radiation Circular Dichroism (SR-CD), X-ray diffraction and solution scattering that are readily accessible at Diamond Light Source. Additionally, built on the Lewis’ group experience, functional mutations will be generated for assays to systematically assess the role/impact of these on activity. In parallel, the constructs will be used for cell biology assays to identify and characterise functional interactions.
In summary, this project aims to highlight the structural and functional properties of human ROCO proteins using multiple biophysical, biochemical and cellular approaches using the expertise provided at Diamond, the Harwell Science and Innovation campus and the University of Reading.
Understanding at a structural level the ability of multi-domain proteins to integrate cellular function such as phosphorylation, GTP hydrolysis and binding to functional partners will be a major step forward in the understanding of cell signalling hubs. This, in turn, will have important implications and medically relevant impact for the development of novel therapies for neurodegenerative disease and cancer.
Applications to this studentship will open in early 2018.
Diamond Light Source Ltd. holds an Athena SWAN Bronze Award, demonstrating their commitment to provide equal opportunities and to advance the representation of women in STEM/M subjects: science, technology, engineering, mathematics and medicine.
Diamond Light Source is the UK's national synchrotron science facility, located at the Harwell Science and Innovation Campus in Oxfordshire.
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