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Cited by 66Cholesterol and Lipid MetabolismLipoproteins and Cardiovascular HealthCellular transport and secretion

Characterization of proprotein convertase subtilisin/kexin type 9 (PCSK9) trafficking reveals a novel lysosomal targeting mechanism via amyloid precursor-like protein 2 (APLP2)

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DeVay, Rachel M., Shelton, David L., Liang, Hong·2013·Journal of Biological Chemistry
DOI 10.1074/jbc.m113.453373PMC PMC3624461
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Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low density lipoprotein receptor protein levels by diverting it to lysosomes. Monoclonal antibody therapeutics aimed to neutralize PCSK9 have been shown to successfully lower serum LDL levels; however, we previously found that such therapeutic antibodies are subject to PCSK9-mediated clearance. In this study, we discovered that PCSK9 interacts via its C-terminal domain directly and in a pH-dependent manner with amyloid precursor protein as well as its closely related family member, amyloid precursor protein-like protein 2. Furthermore, we determined that amyloid precursor protein-like protein-2, but not amyloid precursor protein, is involved in mediating postendocytic delivery of PCSK9 to lysosomes and is therefore important for PCSK9 function. Based on our data, we propose a model for a lysosomal transport complex by which a soluble protein can target another protein for degradation from the luminal side of the membrane by bridging it to a lysosomally targeted transmembrane protein.

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  • PCSK9 interacts with several proteins with known roles in neuronal survival, differentiation, migration and plasticity, including APP, APLP2, sortilin, heparan sulfate proteoglycans, VLDLR and ApoER2.

    “PCSK9 interacts with several proteins with known roles in neuronal survival, differentiation, migration and plasticity, including amyloid precursor protein (APP), amyloid precursor-like protein 2 (APLP2), sortilin (DeVay et al., 2013; Gustafsen et al., 2014; Butkinaree et al., 2015; Fu et al., 2017)”

    From PCSK9 deficiency alters brain lipid composition without affecting brain development and function (2023) · cites this paper as DeVay et al., 2013

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Authors
DeVay, R. M., Shelton, D. L., & Liang, H.
Affiliations
Pfizer (United States) (US)
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2013-04
Volume
288
Issue
15
Pages
10805-10818
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m113.453373
PMC
PMC3624461
OpenAlex
W2006492573
Cited by
66
References
2
Citations by year
2026: 3 · 2025: 1 · 2024: 6 · 2023: 5 · 2022: 2 · 2021: 4 · 2020: 2 · 2019: 2 · 2018: 6 · 2017: 7 · 2016: 6 · 2015: 9 · 2014: 5 · 2013: 8
FWCI
8.50
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
PCSK9, APLP2, amyloid precursor protein, lysosomal targeting, protein trafficking, LDL receptor degradation, C-terminal domain
MeSH terms
Proprotein Convertase 9, Animals, Endocytosis, Humans, Hydrogen-Ion Concentration, Lysosomes, Models, Biological, Nerve Tissue Proteins, Serine Endopeptidases, Amyloid beta-Protein Precursor, Protein Transport, Proprotein Convertases, Mice, Hep G2 Cells, Proteolysis

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