Cross-Reactivity in Protein-Protein Interactions: Studies of T Cell Receptor/Peptide-Mhc Complexes and of Measles Virus Entry by Leremy A Colf
Cross-reactivity in protein-protein interactions can be defined as one receptor recognizing two distinct ligands, or one ligand engaging two distinct receptors. Specificity, in turn, can be defined as an exclusive, pairwise interaction of receptor and ligand with little or no tolerance for genetic or structural deviation. In this work, I have examined systems that are both cross-reactive in having multiple binding partners, but are highly specific as per each of those interactions. I have determined the X-ray crystal structure of the 2C T cell receptor in complex with its foreign, allogeneic ligand, the H-2Ld MHC presenting the QL9 peptide. The observed binding orientation of 2C was markedly different from the previously-described footprint of 2C binding its self ligand, H-2Kb-dEV8, as were the thermodynamics of the interactions. Divergent footprints were observed despite highly similar MHC surfaces presented to the TCR. Three affinity-matured versions of 2C were also crystallized in complex with Ld-QL9, where mutations were contained in the CDR3alpha loop of the TCR. In all cases, the wild-type binding footprint persisted despite binding affinity increases up to 100 fold. Thus, it appears that germline-encoded interactions between the TCR and MHC play a determining role in TCR/pMHC binding orientations. Cross-reactivity for Ld-QL9 was accomplished through distinct interactions via the CDR3 loops. Each TCR had a different method of altering recognition, indicating that cross-reactivity is defined by multiple, specific interactions rather than broad degeneracy. Additionally, I determined the crystal structure of the measles virus hemagglutinin. While exhibiting the overall neuraminidase fold, MVH has lost all neuraminidase function. Instead, MVH has evolved the ability, unique among hemagglutinin and neuraminidase proteins, of attaching to host cells through protein-protein interactions. MVH engages two distinct cellular receptors for attachment and entry, with spatially distinct interaction sites for each receptor. In contrast to other hemagglutinins and neuraminidases, which bind sialic acid in an indiscriminant, degenerate manner, MVH binds each of its receptors with high specificity. Thus, cross-reactivity is attained through spatially distinct sites rather than alternative engagement at a single site. The findings presented in this thesis argue that cross-reactivity in protein-protein interactions can occur through a number of mechanisms, including alternative engagement of similar surfaces or evolution of multiple distinct binding sites. Thus cross-reactivity as observed in these systems does not support theories of molecular mimicry or broad degeneracy, but rather supports individual cases of multiple-specificity interactions.
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