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.

Yamamoto, K; Owen, K; Parker, A; Scilabra, S; Dudhia, J; Strickland, D; Troeberg, L; Nagase, H

Journal article

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.

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 tandfrac12; 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.

Publication status:: Published

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APA Style

Yamamoto, K., Owen, K., Parker, A., Scilabra, S., Dudhia, J., Strickland, D., Troeberg, L., & Nagase, H. (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. Journal of Biological Chemistry, 289(10), 6462–6474.

MLA Style

Yamamoto, K., et al. “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.” Journal of Biological Chemistry, vol. 289, no. 10, American Society for Biochemistry and Molecular Biology Inc., 2014, pp. 6462–74.

Chicago Style

Yamamoto, K, K Owen, A Parker, S Scilabra, J Dudhia, D Strickland, L Troeberg, and H Nagase. 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.” Journal of Biological Chemistry 289 (10): 6462–74.
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