NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor.

Chen, W J; Goldstein, J L; Brown, M S

doi:10.1016/s0021-9258(19)39742-x

Cited by 731

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor.

Chen, W J, Goldstein, J L, Brown, M S·1990·Journal of Biological Chemistry

DOI 10.1016/s0021-9258(19)39742-x

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Abstract

Rapid internalization of the cell surface low density lipoprotein (LDL) receptor requires the first 22 amino acids of the cytoplasmic domain (residues 790-811), which must include an aromatic residue at position 807. In the human LDL receptor, this position is part of a tetrameric sequence, NPVY. A similar tetramer, NPXY (where X stands for any amino acid), is conserved in LDL receptors from six species (including Xenopus laevis) and in two members of the LDL receptor gene family, human LDL receptor-related protein and rat GP330. To determine whether the NPXY sequence is necessary for coated pit-mediated internalization, we used oligonucleotide-directed mutagenesis to substitute alanines for individual amino acids in the cytoplasmic tail of the human LDL receptor. Substitution of alanine for Asn804, Pro805, or Tyr807 (but not Val806) markedly reduced internalization. Only one other amino acid in the cytoplasmic 22-mer (Phe802) was important for internalization. A review of published data revealed NPXY sequences in cytoplasmic domains of at least 10 other cell surface proteins, including tyrosine kinase-linked receptors of the epidermal growth factor and insulin receptor family, the beta-subunits of three integrin receptors, and the amyloid A4 precursor protein. This occurrence is much more frequent than would be expected by chance alone. The possibility of a conditional role for the NPXY sequence in ligand-independent internalization of these proteins is discussed.

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The cytoplasmic tail of the LDLR contains an NPVY sequence that is required for LDLR-mediated endocytosis.
“The cytoplasmic tail of the LDLR contains an NPVY sequence that is required for LDLR-mediated endocytosis (9”
From ARH Is a Modular Adaptor Protein That Interacts with the LDL Receptor, Clathrin, and AP-2 (2002) · cites this paper as [10]
Systematic mutagenesis of amino acids flanking Tyr-807 in the LDLR cytoplasmic tail indicates that the sequence FDNPVY functions as the internalization signal.
“Systematic mutagenesis of the amino acids flanking the Tyr-807 in the cytoplasmic tail of the LDLR indicates that the sequence FDNPVY functions as the internalization signal (9”
From ARH Is a Modular Adaptor Protein That Interacts with the LDL Receptor, Clathrin, and AP-2 (2002) · cites this paper as [10]
Substituting alanine for the valine residue reportedly reduces internalization by only 35%.
“Similarly, substituting alanine for the valine residue, which is poorly conserved in the NPVY (or NPXY) motif in different proteins, has little effect on the interaction between SNX17 and the cytoplasmic tail, reducing it by only 20% and reportedly reducing internalization by only 35% (10).”
From Sorting Motifs in the Intracellular Domain of the Low Density Lipoprotein Receptor Interact with a Novel Domain of Sorting Nexin-17 (2004) · cites this paper as [10]
The same substitutions (Asn-804, Pro-805, or Tyr-807) were reported to reduce internalization by 65-85%.
“the same substitutions were reported to reduce internalization by 65-85% (10).”
From Sorting Motifs in the Intracellular Domain of the Low Density Lipoprotein Receptor Interact with a Novel Domain of Sorting Nexin-17 (2004) · cites this paper as [10]

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Authors: Chen, W. J., Goldstein, J. L., & Brown, M. S.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 1990-02
Volume: 265
Issue: 6
Pages: 3116-3123
ISSN: 0021-9258
DOI: 10.1016/s0021-9258(19)39742-x
Cited by: 731
References: 1
Language: en
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 11230 d)

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NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor.

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