Analyzing the protease web in skin: meprin metalloproteases are activated specifically by KLK4, 5 and 8 vice versa leading to processing of proKLK7 thereby triggering its activation

Ohler, Anke; Debela, Mekdes; Wagner, Sabine G.; Magdolen,; Becker‐Pauly, Christoph

doi:10.1515/bc.2010.023

Cited by 75 publications

(66 citation statements)

References 23 publications

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“…The activity of meprin ␤, which includes s a transmembrane region and a C-terminal cytosolic part, is dependent on various factors. First, it has to be activated by limited proteolysis, which is done by tryptic proteases like kallikreins (35). Furthermore, it is known that it can be released from the cell surface by ectodomain shedding because of TACE activity (6).…”

Section: Discussionmentioning

confidence: 99%

Metalloprotease Meprin β Generates Nontoxic N-terminal Amyloid Precursor Protein Fragments in Vivo

Jefferson

Čaušević

Keller³

et al. 2011

Journal of Biological Chemistry

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Identification of physiologically relevant substrates is still the most challenging part in protease research for understanding the biological activity of these enzymes. The zinc-dependent metalloprotease meprin ␤ is known to be expressed in many tissues with functions in health and disease. Here, we demonstrate unique interactions between meprin ␤ and the amyloid precursor protein (APP). Although APP is intensively studied as a ubiquitously expressed cell surface protein, which is involved in Alzheimer disease, its precise physiological role and relevance remain elusive. Based on a novel proteomics technique termed terminal amine isotopic labeling of substrates (TAILS), APP was identified as a substrate for meprin ␤. Processing of APP by meprin ␤ was subsequently validated using in vitro and in vivo approaches. N-terminal APP fragments of about 11 and 20 kDa were found in human and mouse brain lysates but not in meprin ␤ ؊/؊ mouse brain lysates. Although these APP fragments were in the range of those responsible for caspase-induced neurodegeneration, we did not detect cytotoxicity to primary neurons treated by these fragments. Our data demonstrate that meprin ␤ is a physiologically relevant enzyme in APP processing.

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Section: Discussionmentioning

confidence: 99%

Metalloprotease Meprin β Generates Nontoxic N-terminal Amyloid Precursor Protein Fragments in Vivo

Jefferson

Čaušević

Keller³

et al. 2011

Journal of Biological Chemistry

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“…Of special interest is the fact that meprins cleave components of the extracellular matrix, in particular the basal lamina but also adhesion proteins at the cell-cell interface (Sterchi et al , 2008 ;Ambort et al , 2010 ;Vazeille et al , 2011 ). Recent proteomics approaches have identifi ed previously known and new physiologically relevant in vivo substrates such as vascular endothelial growth factor (Sch ü tte et al, 2010 ), amyloid precursor protein (Jefferson et al , 2011 ), procollagens I and III (Kronenberg et al , 2010 ), interleukin-1 β (Herzog et al , 2005 ), interleukin 18 (Banerjee and Bond , 2008 ), prokallikrein 7 (Ohler et al , 2010 ), and fi broblast growth factor 19 (Becker -Pauly et al, 2011 ).…”

Section: Introduction: a Short Historical Backgroundmentioning

confidence: 99%

Functional and structural insights into astacin metallopeptidases

Gomis‐Rüth

Trillo-Muyo

Stöcker

2012

Biological Chemistry

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The astacins are a family of multi-domain metallopeptidases with manifold functions in metabolism. They are either secreted or membrane-anchored and are regulated by being synthesized as inactive zymogens and also by colocalizing protein inhibitors. The distinct family members consist of N-terminal signal peptides and pro-segments, zincdependent catalytic domains, further downstream extracellular domains, transmembrane anchors, and cytosolic domains. The catalytic domains of four astacins and the zymogen of one of these have been structurally characterized and shown to comprise compact ∼ 200-residue zinc-dependent moieties divided into an N-terminal and a C-terminal sub-domain by an active-site cleft. Astacins include an extended zinc-binding motif (HEXXHXXGXXH) which includes three metal ligands and groups them into the metzincin clan of metallopeptidases. In mature, unbound astacins, a conserved tyrosine acts as an additional zinc ligand, which is swung out upon substrate or inhibitor binding in a ' tyrosine switch ' motion. Other characteristic structural elements of astacin catalytic domains are three large α -helices and a fi ve-stranded β -sheet, as well as two or three disulfi de bonds. The N-terminal pro-segments are variable in length and rather unstructured. They inhibit the catalytic zinc following an ' aspartate-switch ' mechanism mediated by an aspartate embedded in a conserved motif (FXGD). Removal of the pro-segment uncovers a deep and extended active-site cleft, which in general shows preference for aspartate residues in the specifi city pocket (S 1 ′ ). Furthermore, astacins undergo major rearrangement upon activation within an ' activation domain, ' and show a slight hinge movement when binding substrates or inhibitors. In this review, we discuss the overall architecture of astacin catalytic domains and their involvement in function and zymogenic activation.

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“…Activation to Mature Meprin β. Activation of meprins requires proteolysis of the N-terminal PD, which is catalyzed by trypsin in the intestinal lumen and kallikrein-related peptidases (KLK-4, -5, and -8) in other tissues (17,51). Comparison of the zymogenic and mature structures, which were obtained in different crystal forms, reveals that in general the dimers (established in MβΔC between symmetry equivalents) fit together with a global rmsd of 1.2 Å for 1,006 common Cα atoms (of 561 + 554 residues in pMβΔC and 533 + 533 in MβΔC; Fig.…”

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confidence: 99%

Structural basis for the sheddase function of human meprin β metalloproteinase at the plasma membrane

Arolas

Broder²,

Jefferson³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Ectodomain shedding at the cell surface is a major mechanism to regulate the extracellular and circulatory concentration or the activities of signaling proteins at the plasma membrane. Human meprin β is a 145-kDa disulfide-linked homodimeric multidomain type-I membrane metallopeptidase that sheds membrane-bound cytokines and growth factors, thereby contributing to inflammatory diseases, angiogenesis, and tumor progression. In addition, it cleaves amyloid precursor protein (APP) at the β-secretase site, giving rise to amyloidogenic peptides. We have solved the X-ray crystal structure of a major fragment of the meprin β ectoprotein, the first of a multidomain oligomeric transmembrane sheddase, and of its zymogen. The meprin β dimer displays a compact shape, whose catalytic domain undergoes major rearrangement upon activation, and reveals an exosite and a sugar-rich channel, both of which possibly engage in substrate binding. A plausible structure-derived working mechanism suggests that substrates such as APP are shed close to the plasma membrane surface following an "N-like" chain trace. P hysiological processes in the extracellular milieu and the circulation require finely tuned concentrations of signal molecules such as cytokines, growth factors, receptors, adhesion molecules, and peptidases. Many of these proteins are synthesized as type-I membrane protein variants or precursors consisting of a glycosylated N-terminal ectoprotein, a transmembrane helix, and a Cterminal cytosolic tail. Their localization at the cell surface restricts their field of action to autocrine or juxtacrine processes. However, to act at a distance in paracrine, synaptic, or endocrine events, they have to be released from the plasma membrane into the extracellular space as soluble factors through "protein ectodomain shedding" (1, 2). This entails limited proteolysis and is a major posttranslational regulation mechanism that affects 2-4% of the proteins on the cell surface, occurs at or near the plasma membrane (3), and apparently follows a common release mechanism (2). It may also proteolytically inactivate proteins to terminate their function on the cell surface (4). Peptidases engaged in such processing are "sheddases" and the most studied transmembrane sheddases are members of the adamalysin/ADAMs (4, 5) and matrix-metalloproteinase (MMP) (6) families within the metzincin clan of metallopeptidases (MPs) (7-9). These include ADAM

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Analyzing the protease web in skin: meprin metalloproteases are activated specifically by KLK4, 5 and 8 vice versa leading to processing of proKLK7 thereby triggering its activation

Cited by 75 publications

References 23 publications

Metalloprotease Meprin β Generates Nontoxic N-terminal Amyloid Precursor Protein Fragments in Vivo

Metalloprotease Meprin β Generates Nontoxic N-terminal Amyloid Precursor Protein Fragments in Vivo

Functional and structural insights into astacin metallopeptidases

Structural basis for the sheddase function of human meprin β metalloproteinase at the plasma membrane

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