000139205 001__ 139205 000139205 005__ 20240321220555.0 000139205 0247_ $$2doi$$a10.1016/j.matbio.2016.07.004 000139205 0247_ $$2pmid$$apmid:27476612 000139205 0247_ $$2ISSN$$a0945-053X 000139205 0247_ $$2ISSN$$a1569-1802 000139205 037__ $$aDZNE-2020-05527 000139205 041__ $$aEnglish 000139205 082__ $$a610 000139205 1001_ $$0P:(DE-2719)2811733$$aScilabra, Simone D$$b0$$eFirst author$$udzne 000139205 245__ $$aDissecting the interaction between tissue inhibitor of metalloproteinases-3 (TIMP-3) and low density lipoprotein receptor-related protein-1 (LRP-1): Development of a 'TRAP' to increase levels of TIMP-3 in the tissue. 000139205 260__ $$aAmsterdam [u.a.]$$bElsevier$$c2017 000139205 264_1 $$2Crossref$$3print$$bElsevier BV$$c2017-05-01 000139205 3367_ $$2DRIVER$$aarticle 000139205 3367_ $$2DataCite$$aOutput Types/Journal article 000139205 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1708603321_31171 000139205 3367_ $$2BibTeX$$aARTICLE 000139205 3367_ $$2ORCID$$aJOURNAL_ARTICLE 000139205 3367_ $$00$$2EndNote$$aJournal Article 000139205 520__ $$aTissue 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. 000139205 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0 000139205 542__ $$2Crossref$$i2017-05-01$$uhttps://www.elsevier.com/tdm/userlicense/1.0/ 000139205 588__ $$aDataset connected to CrossRef, PubMed, 000139205 650_7 $$2NLM Chemicals$$aLRP1 protein, human 000139205 650_7 $$2NLM Chemicals$$aLow Density Lipoprotein Receptor-Related Protein-1 000139205 650_7 $$2NLM Chemicals$$aReceptors, Artificial 000139205 650_7 $$2NLM Chemicals$$aRecombinant Proteins 000139205 650_7 $$2NLM Chemicals$$aTIMP3 protein, human 000139205 650_7 $$2NLM Chemicals$$aTissue Inhibitor of Metalloproteinase-3 000139205 650_2 $$2MeSH$$aAnimals 000139205 650_2 $$2MeSH$$aBinding Sites 000139205 650_2 $$2MeSH$$aCOS Cells 000139205 650_2 $$2MeSH$$aCell Line, Tumor 000139205 650_2 $$2MeSH$$aChlorocebus aethiops 000139205 650_2 $$2MeSH$$aEndocytosis 000139205 650_2 $$2MeSH$$aEpithelial Cells: cytology 000139205 650_2 $$2MeSH$$aEpithelial Cells: metabolism 000139205 650_2 $$2MeSH$$aExtracellular Matrix: chemistry 000139205 650_2 $$2MeSH$$aExtracellular Matrix: metabolism 000139205 650_2 $$2MeSH$$aGene Expression Regulation 000139205 650_2 $$2MeSH$$aHEK293 Cells 000139205 650_2 $$2MeSH$$aHumans 000139205 650_2 $$2MeSH$$aKinetics 000139205 650_2 $$2MeSH$$aLow Density Lipoprotein Receptor-Related Protein-1: genetics 000139205 650_2 $$2MeSH$$aLow Density Lipoprotein Receptor-Related Protein-1: metabolism 000139205 650_2 $$2MeSH$$aMolecular Sequence Annotation 000139205 650_2 $$2MeSH$$aNeuroglia: cytology 000139205 650_2 $$2MeSH$$aNeuroglia: metabolism 000139205 650_2 $$2MeSH$$aProtein Binding 000139205 650_2 $$2MeSH$$aProtein Interaction Domains and Motifs 000139205 650_2 $$2MeSH$$aProtein Interaction Mapping 000139205 650_2 $$2MeSH$$aProtein Transport 000139205 650_2 $$2MeSH$$aReceptors, Artificial: genetics 000139205 650_2 $$2MeSH$$aReceptors, Artificial: metabolism 000139205 650_2 $$2MeSH$$aRecombinant Proteins: genetics 000139205 650_2 $$2MeSH$$aRecombinant Proteins: metabolism 000139205 650_2 $$2MeSH$$aSignal Transduction 000139205 650_2 $$2MeSH$$aSolubility 000139205 650_2 $$2MeSH$$aTissue Inhibitor of Metalloproteinase-3: genetics 000139205 650_2 $$2MeSH$$aTissue Inhibitor of Metalloproteinase-3: metabolism 000139205 650_2 $$2MeSH$$aTransfection 000139205 7001_ $$0P:(DE-HGF)0$$aYamamoto, Kazuhiro$$b1 000139205 7001_ $$0P:(DE-2719)2811056$$aPigoni, Martina$$b2$$udzne 000139205 7001_ $$0P:(DE-HGF)0$$aSakamoto, Kazuma$$b3 000139205 7001_ $$0P:(DE-2719)2810938$$aMüller, Stephan A$$b4$$udzne 000139205 7001_ $$0P:(DE-2719)9000246$$aPapadopoulou, Alkmini$$b5$$udzne 000139205 7001_ $$0P:(DE-2719)2181459$$aLichtenthaler, Stefan F$$b6$$udzne 000139205 7001_ $$0P:(DE-HGF)0$$aTroeberg, Linda$$b7 000139205 7001_ $$0P:(DE-HGF)0$$aNagase, Hideaki$$b8 000139205 7001_ $$0P:(DE-HGF)0$$aKadomatsu, Kenji$$b9 000139205 77318 $$2Crossref$$3journal-article$$a10.1016/j.matbio.2016.07.004$$b : Elsevier BV, 2017-05-01$$p69-79$$tMatrix Biology$$v59$$x0945-053X$$y2017 000139205 773__ $$0PERI:(DE-600)2005263-7$$a10.1016/j.matbio.2016.07.004$$gVol. 59, p. 69 - 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