Maturation of Secreted Meprin α during Biosynthesis: Role of the Furin Site and Identification of the COOH-Terminal Amino Acids of the Mouse Kidney Metalloprotease Subunit

Tang, Jie; Bond, Judith S.

doi:10.1006/abbi.1997.0453

Cited by 32 publications

(11 citation statements)

References 33 publications

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“…If this scenario is operative, the integrity of the secretase-regulated pathway must be quite high as no increase in EGFP-ZP3 was observed at the plasma membrane of cells expressing the mutant furin. Of note is the presence of unutilized furin cleavage sites in several other secreted proteins, including the metalloprotease meprin A, human immunodeficiency virus type 1 envelope protein gp160, and the thyrotropin receptor (5,14,21,38). A further complication to our understanding of the formation of the zona pellucida is the observation that nonmammalian vertebrates have similar extracellular matrices that surround their eggs and are composed of proteins homologous to ZP1, ZP2, and ZP3.…”

Section: Discussionmentioning

confidence: 99%

Conserved Furin Cleavage Site Not Essential for Secretion and Integration of ZP3 into the Extracellular Egg Coat of Transgenic Mice

Zhao

Gold

Ginsberg

et al. 2002

Molecular and Cellular Biology

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The extracellular zona pellucida surrounding mammalian eggs is formed by interactions of the ZP1, ZP2, and ZP3 glycoproteins. Female mice lacking ZP2 or ZP3 do not form a stable zona matrix and are sterile. The three zona proteins are synthesized in growing oocytes and secreted prior to incorporation into the zona pellucida. A well-conserved furin site upstream of a transmembrane domain near the carboxyl terminus of each has been implicated in the release of the zona ectodomains from oocytes. However, mutation of the furin site (RNRR 3 ANAA) does not affect the intracellular trafficking or secretion of an enhanced green fluorescent protein (EGFP)-ZP3 fusion protein in heterologous somatic cells. After transient expression in growing oocytes, normal EGFP-ZP3 and mutant EGFP-ZP3 associate with the inner aspect of the zona pellucida, which is distinct from the plasma membrane. These in vitro results are confirmed in transgenic mice expressing EGFP-ZP3 with or without the mutant furin site. In each case, EGFP-ZP3 is incorporated throughout the width of the zona pellucida and the transgenic mice are fertile. These results indicate that the zona matrix accrues from the inside out and, unexpectedly, suggest that cleavage at the furin site is not required for formation of the extracellular zona pellucida surrounding mouse eggs.Extracellular matrices provide assorted roles in biology, and the mechanisms of their formation appear quite disparate. The matrix that surrounds vertebrate eggs and early embryos is variously known as the vitelline envelope, the perivitelline membrane, or the zona pellucida. The component parts are most commonly synthesized and secreted from female germ cells, but in some vertebrates they are produced in the somatic compartment of the ovary or in the liver, which requires both transport to the egg and assembly on its surface. Although the molecular biology of the mouse egg coat has been well studied, little is known about the intracellular protein trafficking of individual components or the mechanisms by which they are secreted to form the insoluble extracellular matrix required for fertilization and embryonic development.The mouse zona pellucida consists of three major sulfated glycoproteins (ZP1, ZP2, and ZP3), each of which is encoded by a single-copy gene in the mouse genome. Although the primary structures of ZP1 (623 amino acids, 68 kDa), ZP2 (713 amino acids, 80 kDa), and ZP3 (424 amino acids, 46 kDa) are distinct, they share certain motifs among themselves, as well as with homologues in other mammals (29). Each zona protein has an N-terminal signal peptide, a signature zona box (260 amino acids with eight conserved cysteine residues, (3), and a transmembrane domain near its carboxyl terminus. The conservation of zona proteins among mammals suggests that the three-dimensional structures of the proteins in each class of zona proteins are similar and that the interactions among classes that effect the supramolecular structure of the zona pellucida may be preserved as well. This hypothesis ha...

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Section: Discussionmentioning

confidence: 99%

Conserved Furin Cleavage Site Not Essential for Secretion and Integration of ZP3 into the Extracellular Egg Coat of Transgenic Mice

Zhao

Gold

Ginsberg

et al. 2002

Molecular and Cellular Biology

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“…The transmembrane and cytosolic domains facilitate this processing by mediating a transitional association of meprin α with chaperones that are resident in the rough endoplasmic reticulum (Hahn, Lottaz et al 1997; Tsukuba, Kadowaki et al 2002). The meprin -specific I-domain is essential for the proteolytic processing of meprin α but the C terminus of the mature subunit is in the TRAF domain, which implies that further proteolytic trimming occurs (Hahn, Lottaz et al 1997; Tang and Bond 1998). If the I-domain is deleted, the mutant protein is retained and accumulates in the rough endoplasmic reticulum and is probably degraded (Hengst and Bond 2004).…”

Section: Meprinsmentioning

confidence: 99%

Meprins, membrane-bound and secreted astacin metalloproteinases

Sterchi

Stöcker

Bond

2008

Molecular Aspects of Medicine

174

176

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The astacins are a subfamily of the metzincin superfamily of metalloproteinases. The first to be characterized was the crayfish enzyme astacin. To date more than 200 members of this family have been identified in species ranging from bacteria to humans. Astacins are involved in developmental morphogenesis, matrix assembly, tissue differentiation and digestion. Family members include the procollagen C-proteinase (BMP1, bone morphogenetic protein 1), tolloid and mammalian tolloidlike, HMP (Hydra vulgaris metalloproteinase), sea urchin BP10 (blastula protein) and SPAN (Strongylocentrotus purpuratus astacin), the 'hatching' subfamily comprising alveolin, ovastacin, LCE, HCE ('low' and 'high' choriolytic enzymes), nephrosin (from carp head kidney), UVS.2 from frog, and the meprins. In the human and mouse genomes, there are six astacin family genes (two meprins, three BMP1/tolloid-like, one ovastacin), but in Caenorhabditis elegans there are 40.Meprins are the only astacin proteinases that function on the membrane and extracellularly by virtue of the fact that they can be membrane-bound or secreted. They are unique in their domain structure and covalent subunit dimerization, oligomerization propensities, and expression patterns. They are normally highly regulated at the transcriptional and post-translational levels, localize to specific membranes or extracellular spaces, and can hydrolyse biologically active peptides, cytokines, extracellular matrix (ECM) proteins and cell-surface proteins. The in vivo substrates of meprins are unknown, but the abundant expression of these proteinases in the epithelial cells of the intestine, kidney and skin provide clues to their functions.

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“…They are evolutionarily related to Matrix Metalloproteases (MMPs) and A Disintegrin And Metalloproteases (ADAMs)1, but possess unique structural and functional properties when compared to other metalloproteases2. Constitutive furin-mediated cleavage of meprin α along the secretory pathway results in the release of the enzyme into the extracellular space3 where it undergoes non-covalent oligomerization and can build huge complexes to form the largest secreted protease known to date45. In contrast, meprin β is found primarily tethered to the cell membrane but, under certain conditions, may be shed from the surface by ADAM10 or ADAM1767.…”

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confidence: 99%

Meprin Metalloproteases Generate Biologically Active Soluble Interleukin-6 Receptor to Induce Trans-Signaling

Arnold

Boll

Rothaug

et al. 2017

Sci Rep

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Soluble Interleukin-6 receptor (sIL-6R) mediated trans-signaling is an important pro-inflammatory stimulus associated with pathological conditions, such as arthritis, neurodegeneration and inflammatory bowel disease. The sIL-6R is generated proteolytically from its membrane bound form and A Disintegrin And Metalloprotease (ADAM) 10 and 17 were shown to perform ectodomain shedding of the receptor in vitro and in vivo. However, under certain conditions not all sIL-6R could be assigned to ADAM10/17 activity. Here, we demonstrate that the IL-6R is a shedding substrate of soluble meprin α and membrane bound meprin β, resulting in bioactive sIL-6R that is capable of inducing IL-6 trans-signaling. We determined cleavage within the N-terminal part of the IL-6R stalk region, distinct from the cleavage site reported for ADAM10/17. Interestingly, meprin β can be shed from the cell surface by ADAM10/17 and the observation that soluble meprin β is not capable of shedding the IL-6R suggests a regulatory mechanism towards trans-signaling. Additionally, we observed a significant negative correlation of meprin β expression and IL-6R levels on human granulocytes, providing evidence for in vivo function of this proteolytic interaction.

show abstract

Maturation of Secreted Meprin α during Biosynthesis: Role of the Furin Site and Identification of the COOH-Terminal Amino Acids of the Mouse Kidney Metalloprotease Subunit

Cited by 32 publications

References 33 publications

Conserved Furin Cleavage Site Not Essential for Secretion and Integration of ZP3 into the Extracellular Egg Coat of Transgenic Mice

Conserved Furin Cleavage Site Not Essential for Secretion and Integration of ZP3 into the Extracellular Egg Coat of Transgenic Mice

Meprins, membrane-bound and secreted astacin metalloproteinases

Meprin Metalloproteases Generate Biologically Active Soluble Interleukin-6 Receptor to Induce Trans-Signaling

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