Goodman, KM; (2012) RET receptor tyrosine kinase architecture, protein interactions and chemical inhibition. Doctoral thesis , UCL (University College London).

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Abstract

The RET receptor tyrosine kinase plays a major role in embryonic and adult vertebrate development. Deregulation of RET signalling leads directly to multiple human diseases. Like many receptor tyrosine kinases, the intracellular tyrosine kinase domain of RET is activated by binding of ligand/co-receptor to its ectodomain (ECD). RET is unique among receptor tyrosine kinases, possessing cadherin-like domains (CLD1–4) within its ECD. This thesis describes the architecture of the RET-ECD elucidated using small- angle X-ray scattering (SAXS). These data reveal the interdomain angles and non- linearity of the four CLDs, as well as the location of the membrane-proximal cysteine rich domain (CRD) packed against CLD4. I use this SAXS-derived model of the RET- ECD together with published crystal structures of a RET ligand and co-receptor, to fit into a negative stain electron microscopy 3D reconstruction of a mammalian ligand/co- receptor/RET-ECD ternary complex. The resulting preliminary pseudo-atomic model contains a two-fold symmetrical RET ternary complex with two RET-ECDs wrapped around a core ligand/co-receptor, making extensive contacts from both the N-terminal CLD1–3 region and the membrane-proximal CRD consistent with previous biochemical data and our antibody-epitope mapping. This thesis describes the first view of the RET- ECD and the ligand/co-receptor/RET ternary complex architecture, with important implications for Hirschsprung’s disease and for understanding how ligand-independent RET activation occurs in type 2 multiple endocrine neoplasias.

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