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The J. D. mutation in familial hypercholesterolemia: Amino acid substitution in cytoplasmic domain impedes internalization of LDL receptors
Abstract
Genomic DNA encompassing the terminal exons of the gene for the low density lipoprotein (LDL) receptor was isolated from J.D., a patient with familial hypercholesterolemia whose receptor fails to cluster in coated pits. The DNA sequence revealed a substitution of a cysteine codon for a tyrosine codon at residue 807 in the cytoplasmic domain of the receptor. We reproduced this substitution through oligonucleotide-directed mutagenesis of the normal human receptor cDNA. Upon transfection into receptor-deficient hamster cells, the cDNA specified a receptor that bound LDL normally, but entered the cell slowly. Electron microscopy showed that this receptor was distributed diffusely over the cell surface, whereas the receptor produced by the normal cDNA was concentrated in coated pits. These results support the hypothesis that cytoplasmic domains direct receptors to coated pits, thereby determining the high rate of receptor internalization in animal cells.
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Internalization of the LDLR occurs via clathrin-coated pits and is mediated by a tyrosine-containing motif (NPXY) in the cytoplasmic tail of the receptor.
“Internalization of the LDLR occurs via clathrin-coated pits and is mediated by a tyrosine-containing motif (NPXY) in the cytoplasmic tail of the receptor (1).”
LDLR mediates the rapid endocytosis of apolipoprotein B-containing lipoproteins.
“The low density lipoprotein receptor (LDLR) 1 mediates the rapid endocytosis of apolipoprotein (apo) B-containing lipoproteins.”
A naturally occurring Y807C mutation in the LDLR NPVY motif prevents LDLRs from clustering, and receptors in cells from this patient are distributed diffusely over the cell surface.
“A naturally occurring mutation that changes the tyrosine of the NPVY motif to cysteine (Y807C) prevents LDLRs from clustering; receptors in cells from this patient are distributed diffusely over the cell surface (11”
From ARH Is a Modular Adaptor Protein That Interacts with the LDL Receptor, Clathrin, and AP-2 (2002) · cites this paper as [11]
The NPVY motif within the C-terminus is critical for internalization of LDLR into clathrin-coated pits.
“The NPVY motif within the C-terminus is critical for the internalization of the receptor into clathrin-coated pits (2–4).”
From Identification of amino acid residues in the MT-loop of MT1-MMP critical for its ability to cleave low-density lipoprotein receptor (2022) · cites this paper as [3]
The LDLR is a key determinant of serum cholesterol homeostasis.
“The LDLR is a key determinant of serum cholesterol homeostasis”
From Endocytic adaptors Arh and Dab2 control homeostasis of circulatory cholesterol (2016) · cites this paper as [10]
Mutations in LDLR that eliminate production of the protein or render the receptor unable to undergo endocytosis attest that LDLR is pivotal in the uptake and removal of LDL from the circulation by both hepatic and peripheral tissues.
“Identification of mutations in LDLR that eliminate the production of the protein or render the receptor unable to undergo endocytosis attests that the LDLR is pivotal in the uptake and removal of LDL from the circulation by both hepatic and peripheral tissues”
From Endocytic adaptors Arh and Dab2 control homeostasis of circulatory cholesterol (2016) · cites this paper as [10]
Recruitment of LDLR relies on an FXNPXY motif recognized by the adaptors Dab2 and ARH.
“recruitment of the LDLR relies on an FXNPXY motif (Davis et al., 1986) recognized by the adaptors Dab2 and ARH.”
From Cargo- and adaptor-specific mechanisms regulate clathrin-mediated endocytosis (2010) · cites this paper as Davis et al., 1986
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Research works printed but not linked: 25
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Metadata
- Authors
- Davis, C. G., Lehrman, M. A., Russell, D. W., Anderson, R. G. W., Brown, M. S., & Goldstein, J. L.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 1986-04
- Volume
- 45
- Issue
- 1
- Pages
- 15-24
- ISSN
- 0092-8674
- Cited by
- 273
- References
- 0
- Language
- en
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