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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
Author(s) -
Wang QingYin,
Manicassamy Balaji,
Yu Xuemei,
Dolmer Klavs,
Gettins Peter G.W.,
Rong Lijun
Publication year - 2002
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1110/ps.0219802
Subject(s) - rous sarcoma virus , chemistry , tryptophan , folding (dsp implementation) , ldl receptor , mutant , protein folding , receptor , biochemistry , amino acid , lipoprotein , cholesterol , gene , electrical engineering , engineering
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.