% IMPORTANT: The following is UTF-8 encoded. This means that in the presence % of non-ASCII characters, it will not work with BibTeX 0.99 or older. % Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or % “biber”. @ARTICLE{Scilabra:139205, author = {Scilabra, Simone D and Yamamoto, Kazuhiro and Pigoni, Martina and Sakamoto, Kazuma and Müller, Stephan A and Papadopoulou, Alkmini and Lichtenthaler, Stefan F and Troeberg, Linda and Nagase, Hideaki and Kadomatsu, Kenji}, title = {{D}issecting the interaction between tissue inhibitor of metalloproteinases-3 ({TIMP}-3) and low density lipoprotein receptor-related protein-1 ({LRP}-1): {D}evelopment of a '{TRAP}' to increase levels of {TIMP}-3 in the tissue.}, journal = {Matrix biology}, volume = {59}, issn = {0945-053X}, address = {Amsterdam [u.a.]}, publisher = {Elsevier}, reportid = {DZNE-2020-05527}, pages = {69-79}, year = {2017}, 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.}, keywords = {Animals / Binding Sites / COS Cells / Cell Line, Tumor / Chlorocebus aethiops / Endocytosis / Epithelial Cells: cytology / Epithelial Cells: metabolism / Extracellular Matrix: chemistry / Extracellular Matrix: metabolism / Gene Expression Regulation / HEK293 Cells / Humans / Kinetics / Low Density Lipoprotein Receptor-Related Protein-1: genetics / Low Density Lipoprotein Receptor-Related Protein-1: metabolism / Molecular Sequence Annotation / Neuroglia: cytology / Neuroglia: metabolism / Protein Binding / Protein Interaction Domains and Motifs / Protein Interaction Mapping / Protein Transport / Receptors, Artificial: genetics / Receptors, Artificial: metabolism / Recombinant Proteins: genetics / Recombinant Proteins: metabolism / Signal Transduction / Solubility / Tissue Inhibitor of Metalloproteinase-3: genetics / Tissue Inhibitor of Metalloproteinase-3: metabolism / Transfection / LRP1 protein, human (NLM Chemicals) / Low Density Lipoprotein Receptor-Related Protein-1 (NLM Chemicals) / Receptors, Artificial (NLM Chemicals) / Recombinant Proteins (NLM Chemicals) / TIMP3 protein, human (NLM Chemicals) / Tissue Inhibitor of Metalloproteinase-3 (NLM Chemicals)}, cin = {AG Lichtenthaler / Ext LMU}, ddc = {610}, cid = {I:(DE-2719)1110006 / I:(DE-2719)5000048}, pnm = {342 - Disease Mechanisms and Model Systems (POF3-342)}, pid = {G:(DE-HGF)POF3-342}, typ = {PUB:(DE-HGF)16}, pubmed = {pmid:27476612}, doi = {10.1016/j.matbio.2016.07.004}, url = {https://pub.dzne.de/record/139205}, }