Kushagra Singhal
Van 't Hoff Institute for Molecular Sciences
University of Amsterdam
Science Park 904
1098 XH Amsterdam
room: C2.219c
phone: (+31) 20 525 6928
k.singhal
uva.nl
Research Summary
- Role of Chaperones in Protein Folding
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Proteins produced in ribosomes emerge as long unfolded or partially folded polypeptide chains and need to acquire fully folded unique and specific 3D structures to perform their respective functions. However, this spontaneous unassisted folding process is also highly prone to misfolding, leading to formation of dysfunctional proteins and aggregates that form amyloid-like fibrils and result in neurodegenerative diseases like Parkinson's disease, Alzheimer's disease etc.
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Special proteins, known as chaperones, are present at the exit tunnel of ribosomes or further downstream in the cells to assist in the folding of these nascent chains through direct guidance in folding or prevention of aggregation and misfolding. Triggerfactor is one such chaperone that is best characterized in bacterial cells (e.g., E. coli) and chloroplasts. It is bound to the ribosome at its exit tunnel and present in bacterial cells as a downstream chaperone to assist in the de novo folding as well as stabilization of native structures of proteins. These chaperone functions are performed independent of ATP through non-covalent interactions with protein chains. Thus, to understand the functioning of trigger factor, it is important to gain an understanding of the sites and nature of protein-chaperone interactions; and in turn, to identify and characterise the potential binding pockets on trigger factor.
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We employ all-atom and advanced molecular dynamics techniques to: characterise the conformational space and surface properties of trigger factor in a salt-solution; provide an insight into the tertiary dynamics involved in the flexibility of trigger factor, and the localisation of interactions that drive these dynamics; characterise the surface properties of trigger factor; investigate the protein-chaperone binding mechanism and identify the binding sites and their nature; and study the direct influence of TF binding on protein folding landscape.