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Bone morphogenetic protein 1 cleaves the linker region between ligand-binding repeats 4 and 5 of the LDL receptor and makes the LDL receptor non-functional
Abstract
The cell-surface low-density lipoprotein receptor (LDLR) internalizes low-density lipoprotein (LDL) by receptor-mediated endocytosis and plays a key role in the regulation of plasma cholesterol levels. The ligand-binding domain of the LDLR contains seven ligand-binding repeats of approximately 40 residues each. Between ligand-binding repeats 4 and 5, there is a 10-residue linker region that is subject to enzymatic cleavage. The cleaved LDLR is unable to bind LDL. In this study, we have screened a series of enzyme inhibitors in order to identify the enzyme that cleaves the linker region. These studies have identified bone morphogenetic protein 1 (BMP1) as being the cleavage enzyme. This conclusion is based upon the use of the specific BMP1 inhibitor UK 383367, silencing of the BMP1 gene by the use of siRNA or CRISPR/Cas9 technology and overexpression of wild-type BMP1 or the loss-of-function mutant E214A-BMP1. We have also shown that the propeptide of BMP1 has to be cleaved at RSRR120↓ by furin-like proprotein convertases for BMP1 to have an activity towards the LDLR. Targeting BMP1 could represent a novel strategy to increase the number of functioning LDLRs in order to lower plasma LDL cholesterol levels. However, a concern by using BMP1 inhibitors as cholesterol-lowering drugs could be the risk of side effects based on the important role of BMP1 in collagen assembly.
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BMP1-mediated cleavage of LDLR releases a small N-terminal fragment of 36-40 kDa and retains a C-terminal fragment of 120 kDa in the plasma membrane.
“The BMP1-mediated cleavage of LDLR releases a small N-terminal fragment of 36–40 kDa and retains a C-terminal fragment of 120 kDa in the plasma membrane (Figure 1I) [37,61].”
From Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation (2024) · cites this paper as [61]
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 [61]
BMP1 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 [61]
The 36-40 kDa N-terminal fragment is present in human urine, likely due to clearance from the blood plasma by the kidneys.
“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 [61]
miR-1908-5p targets TGF-β mRNA, an activator of BMP1, which promotes cleavage and functional inactivation of the LDLR.
“miR-1908-5p targets TGF-β mRNA, an activator of the metalloprotease BMP1, which, as discussed below, promotes cleavage and functional inactivation of the LDLR [56,57].”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [57]
Overexpression of BMP1 promotes activity-dependent cleavage of the LDLR, reducing the levels of full-length LDLR in HepG2 cells.
“Third, overexpression of BMP1 promotes activity-dependent cleavage of the LDLR, reducing the levels of full-length LDLR in HepG2 cells [57].”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [57]
The BMP1 inhibitor UK383367 increases the amount of intracellular full-length LDLR while reducing the appearance of the LA 1-4 fragment in CHO cells.
“First, the BMP1 inhibitor UK383367 increases the amount of intracellular full-length LDLR while reducing the appearance of the LA 1-4 fragment in CHO cells [57].”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [57]
siRNA-mediated silencing or ablation of BMP1 in HepG2 and CHO cells increased the levels of full-length LDLR and dramatically decreased the appearance of the truncated LDLR.
“Second, siRNA-mediated silencing or ablation of BPM1 in HepG2 and CHO cells increased the levels of full-length LDLR and dramatically decreased the appearance of the truncated LDLR [56,57].”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [57]
Two independent research groups identified BMP1 as the enzyme responsible for cleavage of LDLR in the linker region between LA4 and LA5.
“Two independent research groups have identified Bone morphogenetic protein 1 (BMP1), a secreted zinc-dependent metalloprotease, as the enzyme responsible for this event [56,57].”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [57]
BMP1 promotes ectodomain shedding of LDLR, decreasing LDLR.
“BMP1 Promotes ectodomain shedding of LDLR ↓ [56,57]”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [57]
The cleaved N-terminal fragment of LDLR is detected in human urine, providing evidence that LDLR is cleaved by BMP1 in humans.
“The cleaved N-terminal fragment of LDLR is detected in human urine, providing evidence that LDLR is cleaved by BMP1 in humans110,111.”
From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [111]
BMP1 cleaves LDLR within its ligand binding domain, releasing a small N-terminal fragment and retaining a 120kDa membrane-bound C-terminal fragment.
“In contrast to MT1-MMP, BMP cleaves LDLR within its ligand binding domain, releasing a small N-terminal fragment, and retaining a 120kDa membrane-bound C-terminal fragment (Fig. 7C)110,111.”
From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [111]
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Self-citationAldworth, H., & Hooper, N. M. (2024) · Biochemical Society Transactions · doi:10.1042/bst20230918 · Cited by 11
Metadata
- Authors
- Strøm, T. B., Bjune, K., & Leren, T. P.
- Affiliations
- Unit for Cardiac and Cardiovascular Genetics, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-10-10
- Volume
- 29
- Issue
- 8
- Pages
- 1229-1238
- ISSN
- 0964-6906
- 1460-2083
- Cited by
- 14
- References
- 2
- Language
- en
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