A5065720626- Protease and Inhibitor Mechanisms
- Reproductive Biology and Fertility
- Peptidase Inhibition and Analysis
- Sperm and Testicular Function
- Enzyme Production and Characterization
- Autophagy in Disease and Therapy
- Signaling Pathways in Disease
- Endoplasmic Reticulum Stress and Disease
- Heat shock proteins research
- Hormonal and reproductive studies
- TGF-β signaling in diseases
- Ovarian function and disorders
- Histone Deacetylase Inhibitors Research
- Renal and related cancers
- Hippo pathway signaling and YAP/TAZ
- Microtubule and mitosis dynamics
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Calcium signaling and nucleotide metabolism
- Cancer-related Molecular Pathways
- Cell Adhesion Molecules Research
- Folate and B Vitamins Research
- Cellular Mechanics and Interactions
- Phytase and its Applications
- Chemical Synthesis and Analysis
Johannes Gutenberg University Mainz
2017-2024
University Medical Center of the Johannes Gutenberg University Mainz
2023-2024
Karolinska Institutet
2019
RWTH Aachen University
2019
Institut de Biologia Molecular de Barcelona
2019
Abstract Vertebrate fetuins are multi-domain plasma-proteins of the cystatin-superfamily. Human fetuin-A is also known as AHSG, α 2 -Heremans-Schmid-glycoprotein. Gene-knockout in mice identified essential for calcified-matrix-metabolism and bone-mineralization. Fetuin-B deficient mice, on other hand, female infertile due to zona pellucida ‘hardening’ caused by metalloproteinase ovastacin unfertilized oocytes. In wildtype fetuin-B inhibits activity thus maintaining oocytes fertilizable. Here...
The multidomain protein BAG3 exerts pleiotropic oncogenic functions in many tumor entities including glioblastoma (GBM). Here, we compared protein-protein interactions either adherently cultured or stem-like U251 GBM cells. In line with BAG3's putative role regulating properties, identified interactors sphere-cultured cells included different stem cell markers (SOX2, OLIG2, and NES), while interactomes of adherent BAG3-proficient indicated a shift toward involvement regulation cilium...
How and where is pro-ovastacin activated how does active ovastacin regulate zona pellucida hardening (ZPH) successful fertilization? Ovastacin partially before exocytosis pre-hardens the (ZP) fertilization. The metalloproteinase stored in cortical granules, it cleaves protein 2 (ZP2) upon fertilization thereby destroys ZP sperm ligand triggers ZPH. Female mice deficient extracellular circulating ovastacin-inhibitor fetuin-B are infertile due to pre-mature We isolated oocytes from wild-type...
Mammalian fetuin-A and fetuin-B are abundant serum proteins with pleiotropic functions. Fetuin-B is a highly selective potent inhibitor of metallopeptidases (MPs) the astacin family, which includes ovastacin in mammals. By inhibiting ovastacin, essential for female fertility. The crystal structure was determined unbound complex archetypal astacin, it found that has tandem cystatin-type modules (CY1 CY2). They connected by an exposed linker rigid, disulfide-linked `CPDCP-trunk', followed...
Significance Membrane-bound metallopeptidases cut substrates as “sheddases” on the cell surface. Due to irreversibility of peptide bond cleavage, they are regulated by specific, colocalizing protein inhibitors. We solved crystal structure complex between ectomoiety human integral membrane sheddase, meprin β (Mβ), and its only reported endogenous inhibitor, fetuin-B (FB), which reveals a large particle ∼250-kDa ∼160-Å maximal dimension. Our results unveiled sophisticated “raised elephant...
Accumulation of misfolded proteins or perturbation calcium homeostasis leads to endoplasmic reticulum (ER) stress and is linked the pathogenesis neurodegenerative diseases. Hence, understanding ability neuronal cells cope with chronic ER fundamental interest. Interestingly, several brain areas uphold functions that enable them resist challenges associated neurodegeneration. Here, we established novel clonal mouse hippocampal (HT22) cell lines are resistant prolonged (chronic) induced by...
Astacin metalloproteinases, in particular meprins α and β, as well ovastacin, are emerging drug targets. Drug-discovery efforts have led to the development of first potent selective inhibitors last few years. However, most recent compounds based on a highly flexible tertiary amine scaffold that could cause metabolic liabilities or decreased potency due entropic penalty upon binding target. Thus, aim this study was discover novel conformationally constrained scaffolds starting points for...
Abstract The co‐chaperone BAG3 is a hub for variety of cellular pathways via its multiple domains and interaction with chaperones the HSP70 family or small HSPs. During aging under stress conditions in particular, BAG3, together molecular chaperones, ensures sequestration aggregated aggregation‐prone ubiquitinated proteins to autophagic‐lysosomal system ubiquitin receptors. Accumulating evidence BAG3‐mediated selective autophagy independent cargo ubiquitination led analyses predicting direct...
After fertilization, the oocyte-specific metalloproteinase ovastacin is released and cleaves zona pellucida protein 2 (ZP2), making impermeable to sperm. Before remains permeable because previously inhibited by fetuin-B. Consequently, in absence of fetuin-B, ZP2 cleavage occurs prematurely leads infertility female fetuin-B deficient mice. In contrast, fetuin-B/ovastacin double-deficient oocytes show a permanently with intact ZP2. this study, we asked if elastic modulus informs about thus...
Abstract Human fetuin-B plays a key physiological role in human fertility through its inhibitory action on ovastacin, member of the astacin family metallopeptidases. The inhibitor consists tandem cystatin-like domains (CY1 and CY2), which are connected by linker containing “CPDCP-trunk” followed C-terminal region (CTR) void regular secondary structure. Here, we solved crystal structure complex with archetypal from crayfish, is useful model ovastacin. Two hairpins CY2, linker, tip...
Abstract Despite huge progress in hormonal therapy and improved vitro fertilization methods, the success rates infertility treatment are still limited. A recently discovered mechanism revealed interplay between plasma protein fetuin‐B cortical granule‐based proteinase ovastacin to be a novel key regulation of fertilization. Upon sperm–egg fusion, cleavage distinct zona pellucida component by destroys sperm receptor, enhances robustness, eventually provides definitive block against...
The metalloproteinase ovastacin is released by the mammalian egg upon fertilization and cleaves a distinct peptide bond in zona pellucida protein 2 (ZP2), component of enveloping extracellular matrix. This limited proteolysis causes hardening, abolishes sperm binding, thereby regulates fertility. Accordingly, this process tightly controlled plasma fetuin-B, an endogenous competitive inhibitor. At present, little known about how cleavage characteristics differ from closely related proteases....
Abstract The encounter of oocyte and sperm is the key event initiating embryonic development in mammals. Crucial functions this existential interaction are determined by proteolytic enzymes, such as acrosin, carried head acrosome, ovastacin, stored cortical granules. Ovastacin released upon fertilisation to cleave zona pellucida, a glycoprotein matrix surrounding oocyte. This limited proteolysis hardens envelope, thereby provides definitive block against polyspermy protects developing...
Abstract The co-chaperone BAG3 is a hub for variety of cellular pathways via its multiple domains and interaction with HSP70 HSPB8. Under aging stress conditions in particular, together molecular chaperones, ensures the sequestration aggregated or aggregation prone ubiquitinated proteins to autophagic-lysosomal system ubiquitin receptors. There are emerging indications that BAG3-mediated selective macroautophagy also copes non-ubiquitinated cargo. Phylogenetically, comprises several highly...
Despite huge progress in hormonal therapy and improved vitro fertilization methods, the success rates infertility treatment are still limited. A recently discovered mechanism revealed interplay between plasma protein fetuin-B cortical granule-based proteinase ovastacin as novel key-mechanism regulation of fertilization. Upon sperm-egg fusion, cleavage a distinct zona pellucida component by destroys sperm receptor, enhances robustness eventually provides definitive block against polyspermy....
<p>Despite huge progress in hormonal therapy and improved vitro fertilization methods, the success rates infertility treatment are still limited. A recently discovered mechanism revealed interplay between plasma protein fetuin-B cortical granule-based proteinase ovastacin as novel key-mechanism regulation of fertilization. Upon sperm-egg fusion, cleavage a distinct zona pellucida component by destroys sperm receptor, enhances robustness eventually provides definitive block against...
Abstract The metalloproteinase ovastacin is released by the mammalian egg upon fertilization and cleaves a distinct peptide bond in zona pellucida protein 2, component of enveloping extracellular matrix. This limited proteolysis causes hardening, abolishes sperm binding thereby regulates fertility. Accordingly, this process tightly controlled plasma fetuin-B, an endogenous competitive inhibitor. At present, little known about how cleavage characteristics differ from closely related...