Structural and functional analysis of a retroviral receptor, Tva

Tva is the cellular receptor for subgroup A avian sarcoma and leucosis virus (ASLV-A). The viral receptor function of Tva is solely determined by a 40-residue cysteine-rich motif called the LDL-A module. In this thesis, an integral approach of molecular biological, biochemical, and biophysical techniques was used to examine the role of calcium in Tva folding, and demonstrated that calcium is not only required for correct protein folding but also necessary for maintaining structural integrity. The solution structure of the Tva LDL-A module, determined by nuclear magnetic resonance (NMR) spectroscopy, provides a working model of how Tva functions as ASLV-A receptor. Moreover, using Tva as a simple model, the possible effects of W33 substitution mutation on LDL-A module folding and ligand binding were examined. The findings suggest that the familial hypercholesterolemia (FH) French Canadian-4 mutation is likely caused by protein misfolding of low-density lipoprotein receptor, thus explaining the defect for this class of FH.