How do cells obey the laws of Chemistry ?
Our research focuses on key Immune regulatory functions, along three main research directions:
T Cell Receptor Signaling
The T cell receptor (TCR) serves as an essential hub for a signal transduction mechanism that elicits cell-mediated immune responses. T cell signaling is governed by the interaction between the TCR on T cells and peptide presenting class I major histocompatibility complex (pMHC-I) on antigen-presenting cells. The signal is relayed from the TCR/pMHC-I interaction through interactions with co-receptors, such as the CD8 and CD3 subunits, to the cytoplasmic side of the T cell. Our aim is to elucidate how the protein-protein interactions of the multiprotein T cell receptor complex result in T cell activation. In particular, we are interested in how the structure and dynamics of the TCR, pMHC-I and CD3 subunits change upon assembly.
Class I MHC Peptide Loading
In the endoplasmic reticulum of the cell, the optimal antigenic peptides for each MHC-I molecule must be selected from a large pool of peptides with different amino acid sequences, lengths, and affinities for the MHC-I. Furthermore, these specific peptides must be loaded onto the MHC-I in an appropriate conformation in order to prolong their presentation on the cell surface. Peptide loading is achieved with the help of molecular chaperones, such as Tapasin, found within the peptide-loading complex. Our aim is to characterize the molecular steps involved in peptide loading onto the MHC-I, and to understand how chaperones can aid the process.
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Viral Immune Evasion Mechanisms
Viral immunoevasins are key molecules employed by viruses to subvert the host immune response during infection. Understanding the molecular basis of their functions is key for explaining how viruses have adapted to specifically infect selected hosts and for the design of new vaccines and other antiviral therapies. Mouse cytomegalovirus (MCMV) has a set of such proteins that specifically interfere with major histocompatibility complex class I (MHC-I) antigen presentation to CD8+ T cells and natural killer (NK) cells. Notwithstanding the large number of genetic and functional studies, the structural biology of immunoevasin specificities and functions is poorly understood, due largely to bottlenecks in co-crystallizing these proteins and their ligands. To bypass this bottleneck, we have developed a new approach that combines sparse datasets from NMR with advanced computational modeling methods. We have previously applied this approach to elucidate the solution structure of the m04/gp34 Immunoevasin, and are currently extending these methods to determine the structures of MHC/Immunoevasin complexes.