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Extracellular proximity labeling reveals an expanded interactome for the matrisome protein TIMP2

ABSTRACT: Classical methods of investigating protein-protein interactions (PPIs) are generally performed in non-living systems, yet in recent years new technologies utilizing proximity labeling (PL) have given researchers the tools to explore proximal PPIs in living systems. PL has distinct advantages over traditional protein interactome studies, such as the ability to identify weak and transient interactions in vitro and in vivo. Most PL studies are performed on targets within or on the cell membrane. We have adapted the original PL method to investigate PPIs within the extracellular compartment, using both BioID2 and TurboID, that we term extracellular PL (ePL). To demonstrate the utility of this modified technique, we investigate the interactome of the widely expressed matrisome protein Tissue inhibitors of metalloproteinases 2 (TIMP2). Tissue inhibitors of metalloproteinases (TIMPs) are a family of multi-functional proteins that were initially defined by their ability to inhibit the enzymatic activity of metalloproteinases (MPs), the major mediators of extracellular matrix (ECM) breakdown and turnover. TIMP2 exhibits a broad expression profile and is often abundant in both normal and diseased tissues. Understanding the functional transformation of matrisome regulators, like TIMP2, during the evolution of tissue microenvironments associated with disease progression is essential for the development of ECM targeted therapeutics. Using carboxyl- and amino-terminal fusion proteins of TIMP2 with BioID2 and TurboID, we describe the TIMP2 proximal interactome. We also illustrate how the TIMP2 interactome changes in the presence of different stimuli, in different cell types, in unique culture conditions (2D vs 3D), and with different reaction kinetics (BioID2 vs. TurboID); demonstrating the power of this technique versus classical PPI methods. We propose that the screening of matrisome targets in disease models using ePL will reveal new therapeutic targets for further comprehensive studies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE252575 | GEO | 2024/01/09

REPOSITORIES: GEO

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Project description:This a model from the article: A theoretical model of type I collagen proteolysis by matrix metalloproteinase (MMP) 2 and membrane type 1 MMP in the presence of tissue inhibitor of metalloproteinase 2. Karagiannis ED, Popel AS. J Biol Chem 2004 Sep 10;279(37):39105-14 15252025 , Abstract: One well documented family of enzymes responsible for the proteolytic processes that occur in the extracellular matrix is the soluble and membrane-associated matrix metalloproteinases. Here we present the first theoretical model of the biochemical network describing the proteolysis of collagen I by matrix metalloproteinases 2 (MMP2) and membrane type 1 matrix metalloproteinases (MT1-MMP) in the presence of the tissue inhibitor of metalloproteinases 2 (TIMP2) in a bulk, cell-free, well stirred environment. The model can serve as a tool for describing quantitatively the activation of the MMP2 proenzyme (pro-MMP2), the ectodomain shedding of MT1-MMP, and the collagenolysis arising from both of the enzymes. We show that pro-MMP2 activation, a process that involves a trimer formation of the proenzyme with TIMP2 and MT1-MMP, is suppressed at high inhibitor levels and paradoxically attains maximum only at intermediate TIMP2 concentrations. We also calculate the conditions for which pro-MMP2 activation is maximal. Furthermore we demonstrate that the ectodomain shedding of MT1-MMP can serve as a mechanism controlling the MT1-MMP availability and therefore the pro-MMP2 activation. Finally the proteolytic synergism of MMP2 and MT1-MMP is introduced and described quantitatively. The model provides us a tool to determine the conditions under which the synergism is optimized. Our approach is the first step toward a more complete description of the proteolytic processes that occur in the extracellular matrix and include a wider spectrum of enzymes and substrates as well as naturally occurring or artificial inhibitors. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Karagiannis ED, Popel AS. (2004) - version01 This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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Extracellular proximity labeling reveals an expanded interactome for the matrisome protein TIMP2

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