Structural and functional studies of cell surface receptors

Thesis

Receptor proteins on the surfaces of cells equip them to communicate with each other and to sense and interact with their environment. One receptor family, the αβ T-cell receptors (TCRs), allow T lymphocytes to detect and respond to pathogens via interactions with antigen-presenting major histocompatibility complex (MHC) molecules on target cells. A degree of TCR cross-reactivity (e.g. through structural similarity between peptide-MHC (pMHC) complexes) is essential to account for all possible pathogens, but can also lead to the misinterpretation of self antigens as foreign, and thereby elicit an autoimmune response, resulting in diseases such as multiple sclerosis (MS). Structural studies of pMHC and TCR-pMHC complexes have been key to developing of an understanding of the molecular basis of TCR cross reactivity, and the first strand of this thesis describes attempts to express and purify a highly cross-reactive MS patient-derived TCR for structural characterisation. The formation, purification and crystallisation of a TCR-self pMHC complex including another autoreactive TCR is also described.

Another family of receptors, the fibronectin leucine-rich transmembrane proteins (FLRTs), has been implicated in roles in embryonic development including cell sorting and adhesion. In the second strand of this thesis, the nature of homotypic interactions between FLRTs, which may underlie adhesion between FLRT transfected cells, is investigated. Biophysical analyses demonstrate that these interactions may be mediated by the extracellular leucine-rich repeat (LRR) domain, and crystal structures of all three FLRT LRR domains suggest how interactions between them may underlie FLRT self-association at the cell surface. Residues which contribute to these interactions are conserved across different members of the FLRT family and different species. These findings confirm that FLRTs induce homotypic cell-cell adhesion, and suggest that this behaviour is mediated by self association at the cell surface via the LRR domain.

Authors: Border, E; Ellen Border

• Publication date: 2012
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: fibronectin leucine-rich transmembrane proteins; cell surface receptors; structural biology; protein-protein interactions; T-cell receptors
• Subjects: Biochemistry; Life Sciences; Crystallography; Membrane proteins