TY - JOUR
T1 - The important role for βVLDLs binding at the fourth cysteine of first ligand-binding domain in the low-density lipoprotein receptor
AU - Iwasaki, Tadao
AU - Takahashi, Sadao
AU - Ishihara, Mitsuaki
AU - Takahashi, Masafumi
AU - Ikeda, Uichi
AU - Shimada, Kazuyuki
AU - Fujino, Takahiro
AU - Yamamoto, Tokuo T.
AU - Hattori, Hiroaki
AU - Emi, Mitsuru
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2004/11
Y1 - 2004/11
N2 - The low-density lipoprotein (LDL) receptor (LDLR) is a crucial role for binding and uptaking apolipoprotein (apo) B-containing lipoproteins, such as very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and LDL. The defect function of the LDLR causes familial hypercholesterolemia (FH), the phenotype of which is elevated plasma cholesterol and premature coronary heart disease (CHD). In the present study, we characterize the role of the cysteine residue of the ligand-binding domain of the LDLR. The mutant LDLR protein of cysteine for serine at codon 25 (25S-LDLR) was expressed in Chinese hamster ovary (CHO) cell line, ldl-A7. By Western blot analysis, the 25S-LDLR was detected with monoclonal antibody IgG-12D10, which reacts with the linker site of the LDLR but not with IgG-C7, which reacts with the NH2 terminus of the receptor. The 25S-LDLR bound LDL similarly to the wild-type LDLR, but the rate of uptake of LDL by the mutant receptor was only about half of that by the wild-type receptor. In contrast, the 25S-LDLR bound and internalized β VLDL more avidly than LDL. These results suggest that the fourth cysteine residue of the first ligand-binding domain of the LDLR might be important for the internalization of atherogenic lipoproteins by vascular cells despite reduced LDL uptake, leading to atherosclerosis and premature cardiovascular disease.
AB - The low-density lipoprotein (LDL) receptor (LDLR) is a crucial role for binding and uptaking apolipoprotein (apo) B-containing lipoproteins, such as very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and LDL. The defect function of the LDLR causes familial hypercholesterolemia (FH), the phenotype of which is elevated plasma cholesterol and premature coronary heart disease (CHD). In the present study, we characterize the role of the cysteine residue of the ligand-binding domain of the LDLR. The mutant LDLR protein of cysteine for serine at codon 25 (25S-LDLR) was expressed in Chinese hamster ovary (CHO) cell line, ldl-A7. By Western blot analysis, the 25S-LDLR was detected with monoclonal antibody IgG-12D10, which reacts with the linker site of the LDLR but not with IgG-C7, which reacts with the NH2 terminus of the receptor. The 25S-LDLR bound LDL similarly to the wild-type LDLR, but the rate of uptake of LDL by the mutant receptor was only about half of that by the wild-type receptor. In contrast, the 25S-LDLR bound and internalized β VLDL more avidly than LDL. These results suggest that the fourth cysteine residue of the first ligand-binding domain of the LDLR might be important for the internalization of atherogenic lipoproteins by vascular cells despite reduced LDL uptake, leading to atherosclerosis and premature cardiovascular disease.
KW - Atherosclerosis
KW - Familial hypercholesterolemia
KW - Ischemic heart disease
KW - Low-density lipoprotein receptor
KW - Mutation
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U2 - 10.1007/s10038-004-0198-4
DO - 10.1007/s10038-004-0198-4
M3 - Article
C2 - 15459764
AN - SCOPUS:15244353780
VL - 49
SP - 622
EP - 628
JO - Journal of Human Genetics
JF - Journal of Human Genetics
SN - 1434-5161
IS - 11
ER -