Characterization of the LDL-A module mutants of Tva, the subgroup A Rous sarcoma virus receptor, and the implications in protein folding.
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.
Wang
Qing-Yin
QY
Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
Manicassamy
Balaji
B
Yu
Xuemei
X
Dolmer
Klavs
K
Gettins
Peter G W
PG
Rong
Lijun
L
D000595:Amino Acid Sequence; D000818:Animals; D030161:Avian Proteins; D001358:Avian Sarcoma Viruses / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011784:Quail; D011973:Receptors, LDL / Q000235:genetics*; D011991:Receptors, Virus / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment
D030161:Avian Proteins; D002135:Calcium-Binding Proteins; D011973:Receptors, LDL; D011991:Receptors, Virus; C088745:Tva receptor