Dissecting the interaction between tissue inhibitor of metalloproteinases-3 (TIMP-3) and low density lipoprotein receptor-related protein-1 (LRP-1): Development of a "TRAP" to increase levels of TIMP-3 in the tissue.

Scilabra, S; Yamamoto, K; Pigoni, M; Sakamoto, K; Müller, S; Papadopoulou, A; Lichtenthaler, S; Troeberg, L; Nagase, H; Kadomatsu, K

Journal article

Dissecting the interaction between tissue inhibitor of metalloproteinases-3 (TIMP-3) and low density lipoprotein receptor-related protein-1 (LRP-1): Development of a "TRAP" to increase levels of TIMP-3 in the tissue.

Abstract:: Tissue inhibitor of metalloproteinases 3 (TIMP-3) is a key regulator of extracellular matrix turnover for its ability to inhibit matrix metalloproteinases (MMPs), adamalysin-like metalloproteinases (ADAMs) and ADAMs with thrombospondin motifs (ADAMTSs). TIMP-3 is a secreted protein whose extracellular levels are regulated by endocytosis via the low-density-lipoprotein receptor-related protein-1 (LRP-1). In this study we developed a molecule able to "trap" TIMP-3 extracellularly, thereby increasing its tissue bioavailability. LRP-1 contains four ligand-binding clusters. In order to investigate the TIMP-3 binding site on LRP-1, we generated soluble minireceptors (sLRPs) containing the four distinct binding clusters or part of each cluster. We used an array of biochemical methods to investigate the binding of TIMP-3 to different sLRPs. We found that TIMP-3 binds to the ligand-binding cluster II of the receptor with the highest affinity and a soluble minireceptor containing the N-terminal half of cluster II specifically blocked TIMP-3 internalization, without affecting the turnover of metalloproteinases. Mass spectrometry-based secretome analysis showed that this minireceptor, named T3TRAP, selectively increased TIMP-3 levels in the extracellular space and inhibited constitutive shedding of a number of cell surface proteins. In conclusion, T3TRAP represents a biological tool that can be used to modulate TIMP-3 levels in the tissue and could be potentially developed as a therapy for diseases characterized by a deficit of TIMP-3, including arthritis.

Publication status:: Published

Peer review status:: Peer reviewed

Actions

Email

Email this record

Send the bibliographic details of this record to your email address.

Your Email
Please enter the email address that the record information will be sent to.

-
Your message (optional)
Please add any additional information to be included within the email.
Cite

Cite this record

APA Style

Scilabra, S., Yamamoto, K., Pigoni, M., Sakamoto, K., Müller, S., Papadopoulou, A., Lichtenthaler, S., Troeberg, L., Nagase, H., & Kadomatsu, K. (2016). Dissecting the interaction between tissue inhibitor of metalloproteinases-3 (TIMP-3) and low density lipoprotein receptor-related protein-1 (LRP-1): Development of a "TRAP" to increase levels of TIMP-3 in the tissue. Matrix Biology, 59, 69–79.

MLA Style

Scilabra, S., et al. “Dissecting the Interaction between Tissue Inhibitor of Metalloproteinases-3 (TIMP-3) and Low Density Lipoprotein Receptor-Related Protein-1 (LRP-1): Development of a ‘TRAP’ to Increase Levels of TIMP-3 in the Tissue.” Matrix Biology, vol. 59, Elsevier, 2016, pp. 69–79.

Chicago Style

Scilabra, S, K Yamamoto, M Pigoni, K Sakamoto, S Müller, A Papadopoulou, S Lichtenthaler, L Troeberg, H Nagase, and K Kadomatsu. 2016. “Dissecting the Interaction between Tissue Inhibitor of Metalloproteinases-3 (TIMP-3) and Low Density Lipoprotein Receptor-Related Protein-1 (LRP-1): Development of a ‘TRAP’ to Increase Levels of TIMP-3 in the Tissue.” Matrix Biology 59: 69–79.
Share
Print