Journal Article

DZNE-2020-05527

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png 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. D. (First author)DZNE* ; Yamamoto, K. ; Pigoni, M.DZNE* ; Sakamoto, K. ; Müller, S. A.DZNE* ; Papadopoulou, A.DZNE* ; Lichtenthaler, S. F.DZNE* ; Troeberg, L. ; Nagase, H. ; Kadomatsu, K.

2017
Elsevier Amsterdam [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.matbio.2016.07.004

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.

Keyword(s): Animals (MeSH) ; Binding Sites (MeSH) ; COS Cells (MeSH) ; Cell Line, Tumor (MeSH) ; Chlorocebus aethiops (MeSH) ; Endocytosis (MeSH) ; Epithelial Cells: cytology (MeSH) ; Epithelial Cells: metabolism (MeSH) ; Extracellular Matrix: chemistry (MeSH) ; Extracellular Matrix: metabolism (MeSH) ; Gene Expression Regulation (MeSH) ; HEK293 Cells (MeSH) ; Humans (MeSH) ; Kinetics (MeSH) ; Low Density Lipoprotein Receptor-Related Protein-1: genetics (MeSH) ; Low Density Lipoprotein Receptor-Related Protein-1: metabolism (MeSH) ; Molecular Sequence Annotation (MeSH) ; Neuroglia: cytology (MeSH) ; Neuroglia: metabolism (MeSH) ; Protein Binding (MeSH) ; Protein Interaction Domains and Motifs (MeSH) ; Protein Interaction Mapping (MeSH) ; Protein Transport (MeSH) ; Receptors, Artificial: genetics (MeSH) ; Receptors, Artificial: metabolism (MeSH) ; Recombinant Proteins: genetics (MeSH) ; Recombinant Proteins: metabolism (MeSH) ; Signal Transduction (MeSH) ; Solubility (MeSH) ; Tissue Inhibitor of Metalloproteinase-3: genetics (MeSH) ; Tissue Inhibitor of Metalloproteinase-3: metabolism (MeSH) ; Transfection (MeSH) ; LRP1 protein, human ; Low Density Lipoprotein Receptor-Related Protein-1 ; Receptors, Artificial ; Recombinant Proteins ; TIMP3 protein, human ; Tissue Inhibitor of Metalloproteinase-3

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Contributing Institute(s):

1. Neuroproteomics (AG Lichtenthaler)
2. Ext Ludwig-Maximilians-University (Ext LMU)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2017

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 10 ; JCR ; Nationallizenz ; SCOPUS ; Web of Science Core Collection

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