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Characterization of the LDL-A module mutants of Tva, the subgroup A Rous sarcoma virus receptor, and the implications in protein folding

¹ Department of Microbiology and Immunology,
² Department of Biochemistry and Molecular Biology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA

Reprint requests to: Lijun Rong, Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, E829 MSB, 835 S. Wolcott Ave., Chicago, IL 60612; e-mail: lijun{at}uic.edu; fax: (312) 996-6415.

Tva is the cellular receptor for subgroup A Rous sarcoma virus (RSV-A), and the viral receptor function is solely determined by a 40-residue motif called the LDL-A module of Tva. In this report, an integral approach of molecular, biochemical, and biophysical techniques was used to examine the role of a well-conserved tryptophan of the LDL-A module of Tva in protein folding and ligand binding. We show that substitution of tryptophan by glycine adversely affected the correct folding of the LDL-A module of Tva, with only a portion giving a calcium-binding conformation. Furthermore, we show that the misfolded LDL-A conformations of Tva could not efficiently bind to its ligand. These results indicate that this conserved tryptophan in the LDL-A module of Tva plays an important role in correct protein folding and ligand recognition. Furthermore, these results 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.

Keywords: Tva; LDL-A module; protein folding; familial hypercholesterolemia (FH)

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