A5073470059- Protease and Inhibitor Mechanisms
- Cell Adhesion Molecules Research
- Peptidase Inhibition and Analysis
- Alzheimer's disease research and treatments
- Cellular transport and secretion
- Galectins and Cancer Biology
- Glycosylation and Glycoproteins Research
- Monoclonal and Polyclonal Antibodies Research
- Trace Elements in Health
- Signaling Pathways in Disease
- HER2/EGFR in Cancer Research
- Cytokine Signaling Pathways and Interactions
- S100 Proteins and Annexins
- Connective tissue disorders research
- Ubiquitin and proteasome pathways
- Cholinesterase and Neurodegenerative Diseases
- Blood Coagulation and Thrombosis Mechanisms
- Cellular Mechanics and Interactions
- Extracellular vesicles in disease
- Nuclear Receptors and Signaling
- Oral microbiology and periodontitis research
- Prion Diseases and Protein Misfolding
- Advanced Proteomics Techniques and Applications
- Biochemical and Structural Characterization
- Cystic Fibrosis Research Advances
Kiel University
2016-2025
Scripps Research Institute
2020-2021
Johannes Gutenberg University Mainz
2006-2015
University of Gothenburg
2014
Imperial College London
2011
ADAM10 and ADAM17 have been shown to contribute the acquired drug resistance of HER2-positive breast cancer in response trastuzumab. The majority inhibitor development has focused on discovery compounds that bind active site zinc, however, recent years, there a shift from secondary substrate binding (exosite) order identify non-zinc-binding molecules. In present work glycosylated, exosite-binding was utilized screen 370,276 MLPCN collection. As result this uHTS effort, selective,...
The mucus that covers and protects the epithelium of intestine is built around its major structural component, gel-forming MUC2 mucin. mucins have traditionally been assumed to be secreted as nonattached. colon has a two-layered system where inner attached epithelium, whereas small normally nonattached mucus. However, meprin β-deficient mice was now found attached. Meprin β an endogenous zinc-dependent metalloprotease shown cleave N-terminal region mucin at two specific sites. When...
Cysteine cathepsins mediate proteome homeostasis and have pivotal functions in diseases such as cancer. To better understand substrate recognition by B, L, S, we applied proteomic identification of protease cleavage sites (PICS) for simultaneous profiling prime non-prime specificity. PICS cathepsin B endopeptidase specificity highlights strong selectivity glycine P3' due to an occluding loop blocking access the primed subsites. In P1', has a partial preference phenylalanine, which is not...
Astacins are secreted and membrane-bound metalloproteases with clear associations to many important pathological physiological processes. Yet only a few substrates described their biological roles enigmatic. Moreover, the lack of knowledge astacin cleavage site specificities hampers assay drug development. Using PICS (proteomic identification protease specificity) TAILS (terminal amine isotopic labeling substrates) degradomics approaches >3000 sites were proteomically identified for five...
Type I fibrillar collagen is the most abundant protein in human body, crucial for formation and strength of bones, skin, tendon. Proteolytic enzymes are essential initiation assembly fibrils by cleaving off propeptides. We report that Mep1a −/− Mep1b mice revealed lower amounts mature compared with WT exhibited significantly reduced deposition along markedly decreased tissue tensile strength. While exploring mechanism this phenotype, we found cleavage full-length procollagen heterotrimers...
The amyloid β (Aβ) peptide, which is abundantly found in the brains of patients suffering from Alzheimer disease, central pathogenesis this disease. Therefore, to understand processing precursor protein (APP) critical importance. Recently, we demonstrated that metalloprotease meprin cleaves APP and liberates soluble N-terminal (N-APP) fragments. In work, present evidence can also process a manner reminiscent β-secretase. We identified cleavage sites sequence wild type Swedish mutant at...
The in vivo roles of meprin metalloproteases pathophysiological conditions remain elusive. Substrates define protease roles. Therefore, to identify natural substrates for human α and β we employed TAILS (terminal amine isotopic labeling substrates), a proteomics approach that enriches N-terminal peptides proteins cleavage fragments. Of the 151 new extracellular identified, it was notable ADAM10 (a disintegrin metalloprotease domain-containing protein 10)-the constitutive α-secretase-is...
Signaling of the cytokine interleukin-6 (IL-6) via its soluble IL-6 receptor (sIL-6R) is responsible for proinflammatory properties and constitutes an attractive therapeutic target, but how sIL-6R generated in vivo remains largely unclear. Here, we use liquid chromatography-mass spectrometry to identify form human serum that originates from proteolytic cleavage, map cleavage site between Pro-355 Val-356, determine occupancy all O- N-glycosylation sites sIL-6R. The metalloprotease a...
Identification of physiologically relevant substrates is still the most challenging part in protease research for understanding biological activity these enzymes. The zinc-dependent metalloprotease meprin β known to be expressed many tissues with functions health and disease. Here, we demonstrate unique interactions between amyloid precursor protein (APP). Although APP intensively studied as a ubiquitously cell surface protein, which involved Alzheimer disease, its precise physiological role...
A Disintegrin and Metalloproteinase 10 (ADAM10) ADAM17 catalyze ectodomain shedding of a number cell surface proteins important for embryonic development tissue homeostasis. Changes in the expression levels or dysregulated proteolytic activity ADAM10 have been shown to play roles multiple diseases such as inflammation, cancer, neurodegenerative disorders. Despite well documented substrate repertoire ADAM17, little is known about their cleavage site specificity. We optimized Q-PICS...
Ectodomain shedding at the cell surface is a major mechanism to regulate extracellular and circulatory concentration or activities of signaling proteins plasma membrane. Human meprin β 145-kDa disulfide-linked homodimeric multidomain type-I membrane metallopeptidase that sheds membrane-bound cytokines growth factors, thereby contributing inflammatory diseases, angiogenesis, tumor progression. In addition, it cleaves amyloid precursor protein (APP) β-secretase site, giving rise amyloidogenic...
Colorectal cancer is treated with antibodies blocking epidermal growth factor receptor (EGF-R), but therapeutic success limited. EGF-R stimulated by soluble ligands, which are derived from transmembrane precursors ADAM17-mediated proteolytic cleavage. In mouse intestinal models in the absence of ADAM17, tumorigenesis was almost completely inhibited, and few remaining tumors were low-grade dysplasia. RNA sequencing analysis demonstrated down-regulation STAT3 Wnt pathway components. Because on...
The metalloprotease meprin β cleaves the Alzheimer's Disease (AD) relevant amyloid precursor protein (APP) as a β-secretase reminiscent of BACE-1, however, predominantly generating N-terminally truncated Aβ2-x variants. Herein, we observed increased endogenous sAPPα levels in brains knock-out (ko) mice compared to wild-type controls. We further analyzed cellular interaction APP and found that cleavage by occurs prior endocytosis. Aβ2-40 variant shows aggregation propensity Aβ1-40 acts even...
Metastasis is the major cause of death in cancer patients. Circulating tumor cells need to migrate through endothelial layer blood vessels escape hostile circulation and establish metastases at distant organ sites. Here, we identified membrane-bound metalloprotease ADAM17 on as a key driver metastasis. We show that TNFR1-dependent cell–induced cell death, extravasation, subsequent metastatic seeding dependent activity ADAM17. Moreover, reveal ADAM17-mediated TNFR1 ectodomain shedding...
Despite the neurodegenerative disorder Alzheimer's disease (AD) is most common form of dementia in late adult life, there currently no therapy available to prevent onset or slow down progression AD. The progressive cognitive decline AD correlates with a successive accumulation cerebral amyloid-β (Aβ) due impaired clearance mechanisms. A significant percentage removed by low-density lipoprotein receptor-related protein 1 (LRP1)-mediated transport across blood-brain barrier (BBB) into...
Several steps of cancer progression, from tumor onset to metastasis, critically involve proteolytic activity. To elucidate the role proteases in cancer, it is particularly important consider single-nucleotide variants (SNVs) that affect active site proteases, thereby influencing cleavage specificity, substrate processing, and thus cell behavior. facilitate systematic studies, we here present a targeted approach determine impact cancer-associated protease (TACAP). Starting with semiautomated...
The metalloproteases meprin alpha and beta are expressed in several tissues, leukocytes, cancer cells. In skin, meprins located separate layers of human epidermis indicating distinct physiological functions, supported by effects on cultured keratinocytes. Meprin induces a dramatic change cell morphology significant reduction number, whereas vitro evidence suggests role for basal keratinocyte proliferation. Meprins secreted as zymogens that activated tryptic proteolytical processing. Here, we...
Meprin α and β, zinc metalloproteinases, play significant roles in inflammation, including inflammatory bowel disease (IBD), possibly by activating cytokines, like interleukin 1β, 18, or tumor growth factor α. Although a number of potential activators for meprins are known, no endogenous inhibitors have been identified. In this work, we analyzed the inhibitory human plasma identified bovine fetuin-A as an meprin inhibitor with K(i) (inhibition constant) 4.2 × 10(-5) M 1.1 10(-6) β. This...
Abstract 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 generated proteolytically from its membrane bound form A Disintegrin And Metalloprotease (ADAM) 10 17 were shown to perform ectodomain shedding of the in vitro vivo . However, under certain conditions not all could be assigned ADAM10/17 activity. Here, we...