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Cited by 51Cellular transport and secretionDrug Transport and Resistance MechanismsCholesterol and Lipid Metabolism

A Sorting Nexin 17‐Binding Domain Within the LRP1 Cytoplasmic Tail Mediates Receptor Recycling Through the Basolateral Sorting Endosome

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Farfán, Pamela, Lee, Jiyeon, Larios, Jorge, Sotelo, Pablo, Bu, Guojun, Marzolo, María‐Paz·2013·Traffic
DOI 10.1111/tra.12076PMC PMC3679278
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Abstract

Sorting nexin 17 (SNX17) is an adaptor protein present in early endosomal antigen 1 (EEA1)‐positive sorting endosomes that promotes the efficient recycling of low‐density lipoprotein receptor‐related protein 1 (LRP1) to the plasma membrane through recognition of the first NPxY motif in the cytoplasmic tail of this receptor. The interaction of LRP1 with SNX17 also regulates the basolateral recycling of the receptor from the basolateral sorting endosome (BSE). In contrast, megalin, which is apically distributed in polarized epithelial cells and localizes poorly to EEA1‐positive sorting endosomes, does not interact with SNX17, despite containing three NPxY motifs, indicating that this motif is not sufficient for receptor recognition by SNX17. Here, we identified a cluster of 32 amino acids within the cytoplasmic domain of LRP1 that is both necessary and sufficient for SNX17 binding. To delineate the function of this SNX17‐binding domain, we generated chimeric proteins in which the SNX17‐binding domain was inserted into the cytoplasmic tail of megalin. This insertion mediated the binding of megalin to SNX17 and modified the cell surface expression and recycling of megalin in non‐polarized cells. However, the polarized localization of chimeric megalin was not modified in polarized Madin‐Darby canine kidney cells. These results provide evidence regarding the molecular and cellular mechanisms underlying the specificity of SNX17‐binding receptors and the restricted function of SNX17 in the BSE.

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  • Stockinger et al discarded the NPxY motif as a SNX17 binding motif for receptors including ApoER2, in part because megalin/LRP2 has three NPxY motifs but did not bind SNX17.

    “However, in contrast, the authors discarded the NPxY motif as a SNX17 binding motif for the receptors - including ApoER2 - in part because megalin/LRP2, another receptor of the LDL-R family, has three NPxY motifs but did not bind SNX17 [27], [37].”

    From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [37]

    The Introduction (page unavailable) says that ApoER2 requires an NPxY motif for SNX17 binding and that megalin/LRP2 has three such motifs but does not bind SNX17; it cites Stockinger et al. for these points. It concludes that the motif is necessary but not sufficient—not that Stockinger et al. discarded it as a binding motif. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • In ApoER2, negatively charged amino acids distal to the NPxY motif are most likely required for a stronger interaction with SNX17.

    “In the case of ApoER2, as was described for LRP1, the presence of negatively charged amino acids distal to the NPxY motif are most likely required for a stronger interaction with SNX17 [37].”

    From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [37]

    The Results section reports that ApoER2 has a similar acidic stretch near its NPxY motif and binds SNX17. Mutagenesis showed that those residues aid binding in LRP1, but the paper does not establish that they are required for stronger binding in ApoER2; that part is an extrapolation. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Authors
Farfán, P., Lee, J., Larios, J., Sotelo, P., Bu, G., & Marzolo, M.
Affiliations
  • Pontificia Universidad Católica de Chile (CL)
  • Washington University in St. Louis (US)
  • Mayo Clinic in Florida (US)
Corresponding author
  • Bu, Guojun
  • Marzolo, María‐Paz
ORCID
Venue
Traffic
Publisher
Wiley
Published
2013-05-08
Volume
14
Issue
7
Pages
823-838
ISSN
  • 1398-9219 (ISSN-L)
  • 1600-0854
DOI
10.1111/tra.12076
PMC
PMC3679278
OpenAlex
W1593343900
Cited by
51
References
1
Citations by year
2026: 2 · 2025: 8 · 2024: 5 · 2023: 1 · 2022: 8 · 2021: 2 · 2020: 4 · 2019: 3 · 2018: 4 · 2017: 4 · 2016: 3 · 2015: 1 · 2014: 4 · 2013: 2
FWCI
1.54
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Traffic (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Americanae (AECID Library) (submittedVersion, other-oa)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders
  • Centre National de la Recherche Scientifique
  • National Institute on Aging (P01AG030128, R01AG027924, R01AG035355)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
LRP1, megalin, receptor recycling, NPXY motif, cytoplasmic tail, adaptor proteins, epithelial polarization, fusion protein
MeSH terms
Amino Acid Sequence, Animals, Binding Sites, Dogs, Humans, Molecular Sequence Data, Protein Binding, Receptors, LDL, Endosomes, Amino Acid Motifs, Protein Transport, Protein Sorting Signals, Tumor Suppressor Proteins, Low Density Lipoprotein Receptor-Related Protein-1, Low Density Lipoprotein Receptor-Related Protein-2, Mice, HEK293 Cells, Sorting Nexins, Madin Darby Canine Kidney Cells

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