The important role for βVLDLs binding at the fourth cysteine of first ligand-binding domain in the low-density lipoprotein receptor

Tadao Iwasaki, Sadao Takahashi, Mitsuaki Ishihara, Masafumi Takahashi, Uichi Ikeda, Kazuyuki Shimada, Takahiro Fujino, Tokuo T. Yamamoto, Hiroaki Hattori, Mitsuru Emi

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)622-628
Number of pages7
JournalJournal of Human Genetics
Volume49
Issue number11
DOIs
Publication statusPublished - 2004 Nov

Keywords

  • Atherosclerosis
  • Familial hypercholesterolemia
  • Ischemic heart disease
  • Low-density lipoprotein receptor
  • Mutation

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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