Sorting Motifs in the Intracellular Domain of the Low Density Lipoprotein Receptor Interact with a Novel Domain of Sorting Nexin-17
Open accessAbstract
The low density lipoprotein (LDL) receptor plays a major role in maintaining human plasma cholesterol levels and mutations in the gene cause familial hypercholesterolemia. The LDL receptor (LDLR) pathway has been well characterized, but little is known of proteins involved in its complex intracellular sorting and trafficking. Sorting nexin 17 (SNX17) has recently been implicated in LDLR intracellular trafficking. We show here that endogenous SNX17 is highly expressed in several cell types and is localized partially in early endosomes. We found that the PX domain of SNX17 is required for its endosomal localization but does not interact directly with the LDL receptor. A novel domain containing a FERM-like domain of SNX17 is needed for its interaction with the LDL receptor. Mutations in the NPXY motif of the LDL-receptor cytoplasmic tail that disrupt internalization also disrupt its interaction with SNX17, whereas mutations elsewhere had little effect. When transiently overexpressed in Chinese hamster ovary cells, SNX17 localized to large vesicular structures and disrupted normal trafficking of the LDL receptor in a PX domain-dependent manner. These results suggest that SNX17 plays a role in the cellular trafficking of the LDL receptor through interaction with the NPVY motif in its cytoplasmic domain and interaction of the PX domain with subcellular membrane compartments.
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The SNX17 PX domain facilitates interaction between SNX17 and PI3P-enriched membranes, particularly early endosome membranes that are positive for EEA1.
“Its PX domain facilitates the interaction between SNX17 and PI3P-enriched membranes, particularly with the early endosome membranes that are positive for EEA1 [27]–[29].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [28]
In “The PX Domain of SNX17 Determines Its Localization in Early Endosomes” (page unavailable), mutating SNX17’s PX domain disrupts endosomal localization, but the intact PX domain alone is insufficient. The paper also reports SNX17 colocalization with EEA1-positive early endosomes. It does not demonstrate that SNX17 binds PI3P-enriched membranes; its explicit PI3P-binding example concerns SNX1. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSNX17 is an adaptor protein localized in the early endosome compartment, mostly due to interaction of its PX domain with early endosomal PI(3)P phospholipids.
“SNX17 is an adaptor protein that is localized in the early endosome compartment [28], [30], [31], mostly due to the interaction of its PX domain with the characteristic early endosomal PI(3)P phospholipids [31], [60].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [28]
The early-endosome localization section reports that vesicular SNX17 colocalizes with an early-endosome marker and that a PX-domain mutation disrupts its localization. It does not show that SNX17 binds PI(3)P or establish that this interaction is the predominant cause of its localization; the PI(3)P-binding result cited there concerns SNX1. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSNX17 interacts with the NPxY motif of LRP1, LDL-R, APP, and β1-integrins.
“This falls in agreement with previous reports showing the interaction of SNX17 with the NPxY motif of LRP1, LDL-R, APP [28], [31], [32], and recently with β1-integrins [33], [34].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [28]
The section headed “The NPVY Motif in the LDL Receptor Is Required for Its Interaction with SNX17” reports that mutations in the LDL receptor’s NPVY motif reduce its interaction with SNX17. This supports the LDL-R part of the claim, but the cited passages do not establish the claimed interactions with LRP1 or APP; β1-integrins are assigned separate citations in the citing sentence. Our copy provides no page number for this section. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe minimal sequence of SNX17 able to interact with the LDL-R receptor is residues 113-389, corresponding to the atypical FERM domain.
“Using a yeast two-hybrid system, it was demonstrated that the minimal sequence of SNX17 able to interact with the LDL-R receptor is the region consisting of residues 113–389 [28], which strictly corresponds to the atypical FERM domain of SNX17 [35].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [28]
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Cites
Haft, C. R., de la Luz Sierra, M., Barr, V. A., Haft, D. H., & Taylor, S. I. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.12.7278 · Cited by 244 · see citing works
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- Campbell, R. E., Tour, O., Palmer, A. E., Steinbach, P. A., Baird, G. S., Zacharias, D. A., and Tsien, R. Y. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 7877-7882
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Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling
McNally, K. E., Faulkner, R., Steinberg, F., Gallon, M., Ghai, R., Pim, D., Langton, P., Pearson, N., Danson, C. M., Nägele, H., et al. (2017) · Nature Cell Biology · doi:10.1038/ncb3610 · Cited by 346 · see citing works
Sorting nexin 17 regulates ApoER2 recycling and reelin signaling
Sotelo, P., Farfán, P., Benitez, M. L., Bu, G., & Marzolo, M.-P. (2014) · PLoS ONE · doi:10.1371/journal.pone.0093672 · Cited by 47 · see citing works
- Authors
- Burden, J. J., Sun, X.-M., García, A. B. G., & Soutar, A. K.
- Affiliations
- Hammersmith Hospital (GB)
- Corresponding author
- Soutar, Anne K.
- ORCID
- Burden, Jemima J.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-04
- Volume
- 279
- Issue
- 16
- Pages
- 16237-16245
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2048636992
- Cited by
- 82
- References
- 1
- Citations by year
- 2025: 10 · 2024: 2 · 2023: 2 · 2022: 8 · 2021: 4 · 2020: 4 · 2019: 2 · 2018: 4 · 2017: 3 · 2016: 1 · 2015: 7 · 2014: 5 · 2013: 4 · 2012: 3
- FWCI
- 1.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Imperial College London
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- LDL receptor, SNX17, PX domain, NPXY motif, receptor internalization, endosomal trafficking, early endosomes, protein-protein interaction, familial hypercholesterolemia, cholesterol homeostasis
- MeSH terms
- Amino Acid Sequence, Animals, Carrier Proteins, Cricetinae, Humans, Molecular Sequence Data, Peptide Mapping, Protein Binding, Receptors, LDL, Signal Transduction, CHO Cells, Protein Structure, Tertiary, Amino Acid Motifs, Protein Transport, Vesicular Transport Proteins, Sorting Nexins
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