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Proteolysis of the low‐density lipoprotein receptor in hepatocytes is mediated by BMP1 but not by other astacin proteases
Abstract
Bone morphogenetic protein 1 (BMP1), a member of the astacin family of zinc‐metalloproteases, proteolytically cleaves the low‐density lipoprotein receptor (LDLR) within its ligand‐binding domain, reducing the binding and cellular uptake of LDL‐cholesterol. Here, we aimed to determine whether astacin proteases other than BMP1 may also cleave LDLR. Although human hepatocytes express all six astacin proteases, including the meprins and mammalian tolloid, we found through pharmacological inhibition and genetic knockdown that only BMP1 contributed to the cleavage of LDLR in its ligand‐binding domain. We also found that the minimum amino acid change required to render mouse LDLR susceptible to cleavage by BMP1 is mutation at the P1′ and P2 positions of the cleavage site. When expressed in cells, the resulting humanised‐mouse LDLR internalised LDL‐cholesterol. This work provides insight into the biological mechanisms regulating LDLR function.
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The 120 kDa LDLR species is primarily a BMP1 cleavage product present at the cell surface and not an intracellular immature form of the receptor.
“However, recent research has shown that this 120 kDa species is in fact primarily a BMP1 cleavage product present at the cell surface and not an intracellular immature form of the receptor [63].”
From Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation (2024) · cites this paper as [63]
The Results section reports that the 130 kDa band in primary hepatocytes is predominantly a BMP1-cleaved LDLR fragment at the cell surface, rather than an intracellular precursor. The paper also describes a 120 kDa BMP1-generated fragment, but the experiment distinguishing a cell-surface cleavage product from an immature receptor specifically concerns the 130 kDa band. (LLM, conf=0.86)
Experimental — accuracy not yet measuredBMP1 is involved in cleaving the LDLR in human primary hepatocytes and in human liver and adrenal samples.
“However, there is evidence that BMP1 is involved in cleaving the LDLR in human primary hepatocytes and in human liver and adrenal samples [37,61,63], and the 36–40 kDa N-terminal fragment is present in human urine, likely due to clearance from the blood plasma by the kidneys [61].”
From Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation (2024) · cites this paper as [63]
The site of cleavage in human LDLR by BMP1 is highly specific, between residues Gly192 and Asp193, with the Asp residue being crucial for cleavage.
“The site of cleavage in human LDLR by BMP1 is highly specific, between residues Gly192 and Asp193, with the Asp residue being crucial for cleavage [37,61,63].”
From Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation (2024) · cites this paper as [63]
BMP1 does not cleave murine LDLR because the cleavage-essential Asp193 is replaced with valine in mice.
“Intriguingly, BMP1 does not cleave murine LDLR [56,108] since the cleavage-essential Asp193 is replaced with valine in mice.”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [108]
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Alabi, A., Xia, X.-D., Gu, H.-M., Wang, F., Deng, S.-J., Yang, N., Adijiang, A., Douglas, D. N., Kneteman, N. M., Xue, Y., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22167-3 · Cited by 63
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The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms
Ndoj, K., Meurs, A., Papaioannou, D., Bjune, K., & Zelcer, N. (2025) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2024.119082 · Cited by 17
Aldworth, H., & Hooper, N. M. (2024) · Biochemical Society Transactions · doi:10.1042/bst20230918 · Cited by 11
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Metadata
- Authors
- Kellett, K. A. B., Fisher, K., Aldworth, H., & Hooper, N. M.
- Affiliations
- Division of Neuroscience, School of Biological Sciences, Faculty of Biology, Medicine and Health University of Manchester UK
- ORCID
- Hooper, Nigel M.
- Venue
- FEBS Letters
- Publisher
- Wiley
- Published
- 2023-06
- Volume
- 597
- Issue
- 11
- Pages
- 1489-1502
- ISSN
- 0014-5793
- 1873-3468
- PMC
- PMC10953048
- Cited by
- 7
- References
- 1
- Language
- en
- Funders
- Biotechnology and Biological Sciences Research Council (BB/S016848/1)
- Medical Research Council (MR/L009625/1)
- University of Manchester
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