TIMP-3 facilitates binding of target metalloproteinases to the endocytic receptor LRP-1 and promotes scavenging of MMP-1.

Scientific Reports
Anna Paola CarrecaSimone D Scilabra

Abstract

Matrix metalloproteinases (MMPs) and the related families of disintegrin metalloproteinases (ADAMs) and ADAMs with thrombospondin repeats (ADAMTSs) play a crucial role in extracellular matrix (ECM) turnover and shedding of cell-surface molecules. The proteolytic activity of metalloproteinases is post-translationally regulated by their endogenous inhibitors, known as tissue inhibitors of metalloproteinases (TIMPs). Several MMPs, ADAMTSs and TIMPs have been reported to be endocytosed by the low-density lipoprotein receptor-related protein-1 (LRP-1). Different binding affinities of these proteins for the endocytic receptor correlate with different turnover rates which, together with differences in their mRNA expression, determines their nett extracellular levels. In this study, we used surface plasmon resonance to evaluate the affinity between LRP-1 and a number of MMPs, ADAMs, ADAMTSs, TIMPs and metalloproteinase/TIMP complexes. This identified MMP-1 as a new LRP-1 ligand. Among the proteins analyzed, TIMP-3 bound to LRP-1 with highest affinity (KD = 1.68 nM). Additionally, we found that TIMP-3 can facilitate the clearance of its target metalloproteinases by bridging their binding to LRP-1. For example, the free form of MMP-1 was...Continue Reading

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Citations

Feb 11, 2021·Pharmaceuticals·Oliver McClurgLinda Troeberg
Feb 14, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Matteo CalligarisSimone Dario Scilabra
Mar 7, 2021·International Journal of Molecular Sciences·Anna Paola CarrecaSimone Dario Scilabra
Jul 17, 2021·Frontiers in Molecular Biosciences·Keron W J RoseDirk Hubmacher

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Methods Mentioned

BETA
surface plasmon resonance
chip
surface
RAP

Software Mentioned

BIOevaluation
Prism
GraphPad
BIAevaluation
SPR

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