The mechanobiology of the T-Cell Receptor: Structurally connecting catch bonds with ligand binding and triggering

The mechanism of the recognition of antigens and the activation of CD3 signaling domains by the T-Cell Receptor (TCR) are studied. The first part is focused to investigate how the information encoded in the peptide is decoded mechanically by the TCR and what is the structural role of catch bonds. It is proposed that TCRs uses catch bonds to determine whether or not the presented antigen is a threat. It is demonstrated for the first time that catch bonds formed experimentally between a TCR and a peptide-loaded major histocompatibility complex (pMHC) can be predicted a priori by using "in silico" biology and that catch bonds are required to effectively recognize epitopes. TCRs must rotate around the pMHC binding axes to form catch bonds and thus induce functional conformational states of the peptide. The second part studies how information read from the TCR distal-membrane binding site is propagated to the CD3 signaling domains. It is proposed the peptide-decoding process and intracellular signaling are connected by conformational changes traveling across the TCR. It is shown that TCRs are deformable proteins that can experience large conformational changes and they use mechanical forces to modulate their conformations. The ability of TCRs to deform without releasing the peptide ligands is the key to understand this complex mechanism. Finally, it is unveiled the molecular mechanism of how TCRs uses their Cβ FG loop to propagate information and interact with the CD3 signaling domains.Ph.D