Proteolysis of the low‐density lipoprotein receptor in hepatocytes is mediated by BMP1 but not by other astacin proteases
Open Access
- 5 June 2023
- journal article
- research article
- Published by Wiley in FEBS Letters
- Vol. 597 (11), 1489-1502
- https://doi.org/10.1002/1873-3468.14667
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.Funding Information
- Biotechnology and Biological Sciences Research Council (BB/S016848/1)
- Medical Research Council (MR/L009625/1)
- University of Manchester
This publication has 21 references indexed in Scilit:
- Reducing Elevated Plasma LDL Cholesterol: The Central Role of the LDL ReceptorClinical Pharmacology & Therapeutics, 2014
- Functional and structural insights into astacin metallopeptidasesBiological Chemistry, 2012
- The bone morphogenetic protein 1/Tolloid-like metalloproteinasesMatrix Biology, 2007
- Potent and Selective Nonpeptidic Inhibitors of Procollagen C-ProteinaseJournal of Medicinal Chemistry, 2007
- The protease domain of procollagen C-proteinase (BMP1) lacks substrate selectivity, which is conferred by non-proteolytic domainsBiological Chemistry, 2007
- Identification of the Minimal Domain Structure of Bone Morphogenetic Protein-1 (BMP-1) for Chordinase ActivityOnline Journal of Public Health Informatics, 2005
- Meprin metalloprotease expression and regulation in kidney, intestine, urinary tract infections and cancerFEBS Letters, 2005
- Characterization of a Novel Gene Product (Mammalian Tolloid-like) with High Sequence Similarity to Mammalian Tolloid/Bone Morphogenetic Protein-1Genomics, 1996
- Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor.Proceedings of the National Academy of Sciences of the United States of America, 1995
- Complementation of mutations in the LDL pathway of receptor-mediated endocytosis by cocultivation of LDL receptor-defective hamster cell mutantsCell, 1983