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Yamamoto, Kazuhiro, Owen, Kathryn, Parker, Andrew E, Scilabra, Simone D, Dudhia, Jayesh, Strickland, Dudley K, Troeberg, Linda 
ORCID: https://orcid.org/0000-0003-0939-4651 and Nagase, Hideaki
(2014)
Low density lipoprotein receptor-related protein 1 (LRP1)-mediated endocytic clearance of a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4):functional differences of non-catalytic domains of ADAMTS-4 and ADAMTS-5 in LRP1 binding.
The Journal of Biological Chemistry, 289 (10).
pp. 6462-6474.
ISSN 0021-9258
Abstract
Degradation of the cartilage proteoglycan aggrecan is an early event in the development of osteoarthritis, and a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and ADAMTS-5 are considered to be the major aggrecan-degrading enzymes. We have recently found that ADAMTS-5 is rapidly endocytosed via low density lipoprotein receptor-related protein 1 (LRP1) and degraded by chondrocytes. Here we report that this regulatory mechanism also applies to ADAMTS-4, although its rate of endocytosis is slower than that of ADAMTS-5. Domain deletion mutagenesis of ADAMTS-4 identified that the cysteine-rich and spacer domains are responsible for binding to LRP1, whereas the thrombospondin 1 and spacer domains are responsible in ADAMTS-5. The estimated t½ value of ADAMTS-4 endocytosis was about 220 min, whereas that of ADAMTS-5 was 100 min. The difference in half-lives between the two enzymes is explained by the 13-fold lower affinity of ADAMTS-4 for LRP1 compared with that of ADAMTS-5. Studies using soluble ligand binding clusters of LRP1 showed that ADAMTS-4 binds to clusters II and IV with similar KD,app values of 98 and 73 nm, respectively, whereas ADAMTS-5 binds to cluster II, III, and IV with KD,app values of 3.5, 41, and 9 nm, respectively. Thus, ADAMTS-5 competitively inhibits ADAMTS-4 endocytosis but not vice versa. This study highlights that the affinity between a ligand and LRP1 dictates the rate of internalization and suggests that LRP1 is a major traffic controller of the two aggrecanases, especially under inflammatory conditions, where the protein levels of ADAMTS-4 increase, but those of ADAMTS-5 do not.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | chemistry,adamts4 protein,adamts5 protein,animals,metabolism,genetics,cells, cultured,endocytosis,half-life,humans,metabolism,metabolism,chemistry,protein binding,sequence deletion,swine |
| Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School |
| UEA Research Groups: | Faculty of Medicine and Health Sciences > Research Groups > Musculoskeletal Medicine Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 08 Jan 2019 12:30 |
| Last Modified: | 19 Oct 2023 02:20 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/69486 |
| DOI: | 10.1074/jbc.M113.545376 |
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