Detection of a secreted metalloprotease within the nuclei of liver cells

Laboratory of Hemostasis, Division of Hematology, Center for Biologic, Food and Drug Administration, Bethesda, Maryland 20892, USA.
Molecular BioSystems (Impact Factor: 3.21). 06/2011; 7(6):2012-8. DOI: 10.1039/c0mb00303d
Source: PubMed


ADAMTS13 is a secreted zinc metalloprotease expressed by various cell types. Here, we investigate its cellular pathway in endogenously expressing liver cell lines and after transient transfection with ADAMTS13. Besides compartmentalizations of the cellular secretory system, we detected an appreciable level of endogenous ADAMTS13 within the nucleus. A positively charged amino acid cluster (R-Q-R-Q-R-Q-R-R) present in the ADAMTS13 propeptide may act as a nuclear localization signal (NLS). Fusing this NLS-containing region to eGFP greatly potentiated its nuclear localization. Bioinformatics analysis suggests that the ADAMTS13 CUB-2 domain has a double-stranded beta helix (DSBH) structural architecture characteristic of various protein-protein interaction modules like nucleoplasmins, class I collagenase, tumor necrosis factor ligand superfamily, supernatant protein factor (SPF) and the B1 domain of neuropilin-2. Based on this contextual evidence and that largely conserved polar residues could be mapped on to a template CUB domain homolog, we hypothesize that a region in the ADAMTS13 CUB-2 domain with conserved polar residues might be involved in protein-protein interaction within the nucleus.

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    • "Although this is an unusual phenomenon, examples of similar protein behaviour do exist. A study of ADAMTS13, a secreted zinc metalloprotease involved in an array of processes including development and angiogenesis, detected the protein in the nucleus of liver cells [49]. Other metalloproteinases, MMP-2 [50] and MMP3 [51], which are involved in extracellular matrix remodeling, were detected in the nucleus of cardiac myocytes and chondrocytic cells, respectively. "
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    • "ADAMTS13 codes for a 190 kD zinc metalloprotease that is secreted primarily from liver cells (Levy et al, 2001; Soejima et al, 2001; Zheng et al, 2001) and is constitutively active in the bloodstream, primarily functioning as the von Willebrand Factor (VWF) cleaving protease. Additionally, ADAMTS13 may serve an array of other important functions, based on evidence that it localizes to the nucleus in liver cells (Hunt et al, 2011) and is secreted by endothelial cells with an unknown function (Turner et al, 2006; Kling et al, 2008). "
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