Integration of structural mass spectrometry and computational methods for the study of early protein misfolding events
Project ID: 2228cd1329 (You will need this ID for your application)
Research Theme: Healthcare Technologies
UCL Lead department: Division of Biosciences
Lead Supervisor: Konstantinos Thalassinos
Project Summary:
Protein unfolding and misfolding events are central to various human diseases, where early oligomers are believed to play a critical role in their cytotoxicity. Traditional structural biology techniques have limitations in studying the dynamic and heterogeneous nature of these systems. Structural mass spectrometry (MS) methods, including ion mobility, top-down, and crosslinking, offer valuable insights into these structures while addressing their flexibility. Cyclic ion mobility, in particular, allows for the precise isolation and analysis of closely related conformers with enhanced resolution. When combined with electron capture dissociation, which selectively breaks covalent bonds while preserving noncovalent interactions, it reveals specific association regions. Another useful method is crosslinking, which identifies interacting amino acids.
While computational strategies and software solutions are well-established for some structural mass spectrometry techniques, there is a need for further advancements, especially in ion mobility. Integrating diverse data sets is also a thriving research area, which we aim to explore in this project.
Our project primarily focuses on developing mass spectrometry and computational methods to study the early oligomers formed by human islet amyloid polypeptide (IAPP). IAPP is a pancreatic hormone comprising 37 amino acids, and its misfolding is linked to β-cell death in the pancreas, a critical factor in type-2 diabetes (T2D). Under normal conditions, IAPP regulates metabolism, but in diabetes, it transforms into insoluble extracellular pancreatic amyloid fibrils through an unknown mechanism. It is widely recognized that early oligomeric states are pivotal in protein self-assembly and the development of amyloid diseases. However, due to the heterogeneity and transient nature of these species, they are challenging to study using conventional techniques, making our research crucial for advancing our understanding.
In the Thalassinos lab you will receive training in cutting-edge MS methods, especially cyclic ion mobility, while in the Fraternali lab, in molecular dynamics and development of integrative modeling methods.