Article
Chemistry, Multidisciplinary
Dachi Wang, Wenxi Wang, Le Fang, Lubin Qi, Yuchao Zhang, Jie Liu, Yuxin Liang, Hongwei Yang, Mengjie Wang, Xiaojian Wei, Ruibin Jiang, Yuan Liu, Wei Zhou, Xiaohong Fang
Summary: Targeted protein degradation (TPD) is an emerging technique for regulating proteins. However, current TPD methods are ineffective against target proteins in membrane organelles like mitochondria. In this study, a mitochondria-targeting protease chimera (MtPTAC) was developed, which can specifically degrade target proteins inside mitochondria. MtPTAC activates the hydrolase activity of mitochondrial caseinolytic protease P (ClpP) and brings target proteins in proximity with ClpP. The study demonstrates the powerful proteolytic ability and potential application of MtPTAC in tumor treatment.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Review
Biochemistry & Molecular Biology
Antonella Cormio, Francesca Sanguedolce, Vito Pesce, Clara Musicco
Summary: ClpP plays a crucial role in regulating mitochondrial function and protein homeostasis, and its overexpression in tumor cells can lead to drug resistance. Modulation of ClpP activity can impair oxidative phosphorylation in cancer cells and induce apoptosis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Mahkameh Abeditashi, Jonasz Jeremiasz Weber, Priscila Pereira Sena, Ana Velic, Maria Kalimeri, Rana Dilara Incebacak Eltemur, Jana Schmidt, Jeannette Huebener-Schmid, Stefan Hauser, Boris Macek, Olaf Riess, Thorsten Schmidt
Summary: The study investigates the role of the nuclear transport receptor KPNB1 in MJD cell models and finds that KPNB1 can modulate the protein levels of ataxin-3 and reduce aggregate load, thereby improving cell viability. Furthermore, the reduction of ataxin-3 induced by KPNB1 appears to be based on protein fragmentation independent of classical MJD-associated proteolytic pathways. These findings suggest KPNB1 as a potential therapeutic target for MJD.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Article
Pharmacology & Pharmacy
Emily M. J. Fennell, Lucas J. Aponte-Collazo, Wimal Pathmasiri, Blake R. Rushing, Natalie K. Barker, Megan C. Partridge, Yuan-Yuan Li, Cody A. White, Yoshimi E. Greer, Laura E. Herring, Stanley Lipkowitz, Susan C. J. Sumner, Edwin J. Iwanowicz, Lee M. Graves
Summary: ClpP activators ONC201 and related small molecules have shown significant anti-cancer potential in vitro and in vivo studies. However, the exact mechanism by which ClpP activation leads to broad anti-cancer activity is still not fully understood. In this study, a multi-omics approach was used to identify the changes in proteomic, transcriptomic, and metabolomic profiles following ClpP activation in triple-negative breast cancer cells. The results showed that ONC201 and TR-57 induced similar effects on mitochondrial processes, cell cycle, and nucleus-related transcripts, and also impacted pathways such as ATF4 activation, heme biosynthesis, and the citrulline/urea cycle.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Multidisciplinary Sciences
Yanpeng Xiong, Shanghong Liu, Jinxin Zheng, Jinlian Chen, Zewen Wen, Xiangbin Deng, Bing Bai, Duoyun Li, Zhijian Yu, Shiqing Han, Xiaoju Liu, Peiyu Li
Summary: Cinacalcet exhibits good inhibitory activity against multi-drug-resistant Gram-positive bacteria and shows rapid and strong bactericidal activity against planktonic and persister cells. It also demonstrates potent inhibition and eradication of mature biofilms. In vivo studies confirm its robust antibacterial activity. These findings suggest that cinacalcet may be a promising new candidate antibiotic to combat infections caused by multidrug-resistant Gram-positive pathogens.
Article
Genetics & Heredity
Xiong Yuan, Wenjie Ma, Shuping Chen, Huiyuan Wang, Chenyi Zhong, Li Gao, Yugui Cui, Danhua Pu, Rongrong Tan, Jie Wu
Summary: This study identified a novel CLPP missense variant in a woman with premature ovarian insufficiency (POI), which may contribute to the development of POI.
FRONTIERS IN GENETICS
(2023)
Review
Biochemistry & Molecular Biology
Mark F. Mabanglo, Vaibhav Bhandari, Walid A. Houry
Summary: The ClpP protease is important for protein homeostasis and regulates key cellular pathways in bacteria and eukaryotes. In mitochondria, it interacts with other proteins to play a role in mitochondrial function. Proteomic studies have identified ClpP substrates involved in essential mitochondrial processes such as the Krebs cycle, oxidative phosphorylation, translation, fatty acid metabolism, and amino acid metabolism.
CURRENT OPINION IN CHEMICAL BIOLOGY
(2022)
Article
Chemistry, Medicinal
Ranran Zhang, Pengyu Wang, Bingyan Wei, Liang Chen, Xiaomin Song, Yihui Pan, Jiahui Li, Jianhua Gan, Tao Zhang, Cai-Guang Yang
Summary: A compound called ZG36 has been found to improve the thermal stability of ClpP in acute myeloid leukemia (AML) cells by directly binding to it. This compound degrades respiratory chain complexes, decreases mitochondrial DNA, and ultimately leads to the collapse of mitochondrial function and death of leukemic cells. In experiments using xenografted mice, ZG36 was also shown to inhibit 3D cell growth and suppress tumorigenesis of AML cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Florian Leisinger, Dzmitry A. Miarzlou, Florian P. Seebeck
Summary: Molecular oxygen is a sustainable oxidation reagent with strong oxidizing properties and stability, ultimately forming water as the reaction product. The activation of O-2 can occur through various pathways, with enzymes typically forming metal-oxygen coordination complexes to facilitate the process. The formylglycine generating enzyme (FGE) demonstrates a unique strategy for activating O-2, involving binding of O-2 near, but not coordinated to, its catalytic copper atom.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Microbiology
Maiken Mellergaard, Sarah Line Skovbakke, Stine Dam Jepsen, Nafsika Panagiotopoulou, Amalie Boge Rud Hansen, Weihua Tian, Astrid Lund, Rikke Illum Hogh, Sofie Hedlund Moller, Romain Guerillot, Ashleigh S. Hayes, Lise Tornvig Erikstrup, Lars Andresen, Anton Y. Peleg, Anders Rhod Larsen, Timothy P. Stinear, Aase Handberg, Christian Erikstrup, Benjamin P. Howden, Steffen Goletz, Dorte Frees, Soren Skov
Summary: This study found that an S. aureus clpP mutant selected during clinical antibiotic therapy inhibits T-cell activity by directly interacting with PD-1 on human T cells, and suggests that therapeutic targeting of PD-1 may be effective against certain staphylococcal infections.
Review
Biotechnology & Applied Microbiology
Astrid Illigmann, Yvonne Thoma, Stefan Pan, Laura Reinhardt, Heike Broetz-Oesterhelt
Summary: The Clp protease system plays a crucial role in bacterial survival by ensuring fast adaptation to environmental changes. It is responsible for protein homeostasis, quality control, and targeted proteolysis, and is essential for regulating various cellular processes in both prokaryotes and eukaryotes. This system not only helps bacteria cope with stress conditions and regulate developmental programs, but also plays a vital role in pathogenic species by controlling virulence factor expression and host colonization.
MICROBIAL PHYSIOLOGY
(2021)
Article
Oncology
Yu Geon Lee, Hui Won Kim, Yeji Nam, Kyeong Jin Shin, Yu Jin Lee, Do Hong Park, Hyun-Woo Rhee, Jeong Kon Seo, Young Chan Chae
Summary: Mitochondrial proteases LONP1 and ClpP work together to alleviate proteotoxic stress and protect mitochondrial functions, supporting cancer cell survival. They target crucial components of mitochondrial functions and have overlapping substrates, such as SHMT2, to regulate cancer cell growth and sensitivity to metabolic stress. Patients with higher expression levels of LONP1 and ClpP have poorer prognosis in prostate cancer, suggesting that targeting the mitochondrial proteostasis network via these proteases could be a potential therapeutic strategy.
Article
Biochemistry & Molecular Biology
Oliver H. Weiergraeber, Dusan Petrovic, Andreas Kislat, Martin Pattky, Judith Fabig, Renu Batra-Safferling, Jan Schulte Am Esch, Karen Haenel, Carolin Huhn, Birgit Strodel, Bernhard Homey, Dieter Willbold
Summary: CCL16 is primarily synthesized by hepatocytes, circulates in the blood as a full-length protein, and the C-terminal extension may impair its biological activity modulation.
Article
Multidisciplinary Sciences
Mansour Aboelenain, Karen Schindler, Cecilia S. Blengini
Summary: Aneuploidy is a major genetic abnormality causing early miscarriage and pregnancy failure in humans, and errors in oocyte meiosis play a significant role in this condition. This article describes three techniques to evaluate SAC integrity in mouse oocytes, which provide insights into the mechanisms needed to produce healthy eggs.
JOVE-JOURNAL OF VISUALIZED EXPERIMENTS
(2022)
Review
Biochemistry & Molecular Biology
Radoslav Petkov, Amy H. Camp, Rivka L. Isaacson, James H. Torpey
Summary: The exploitation of a cell's natural degradation machinery for therapeutic purposes is an exciting research area in its infancy with respect to bacteria. Current strategies targeting the ClpCP system include the use of natural product antibiotics or acyldepsipeptides to modulate its activity, as well as the development of BacPROTACs to trigger specific protein degradation through the hijacking of the ClpCP machinery.
BIOCHEMICAL JOURNAL
(2023)
Article
Biochemical Research Methods
Christopher M. Scheidler, Milan Vrabel, Sabine Schneider
ACS SYNTHETIC BIOLOGY
(2020)
Article
Biochemistry & Molecular Biology
Isabel Y. Buchsbaum, Pavel Kielkowski, Grazia Giorgio, Adam C. O'Neill, Rossella Di Giaimo, Christina Kyrousi, Shahryar Khattak, Stephan A. Sieber, Stephen P. Robertson, Silvia Cappello
Article
Biochemistry & Molecular Biology
Miriam Pfab, Pavel Kielkowski, Ralph Krafczyk, Wolfram Volkwein, Stephan A. Sieber, Juergen Lassak, Kirsten Jung
Summary: The study identified the kinetics of EpmA catalyzing the post-translational modification of K34 in EF-P, showing that natural (R)-beta-lysylation was more effective than synthetic modifications. This work not only provides new insights into the function of EF-P, but also introduces a new approach for post-translationally modifying proteins using EpmA.
Article
Cell Biology
Bruno Pinheiro, Christopher M. Scheidler, Pavel Kielkowski, Marina Schmid, Ignasi Forne, Suhui Ye, Norbert Reiling, Eriko Takano, Axel Imhof, Stephan A. Sieber, Sabine Schneider, Kirsten Jung
Article
Biochemistry & Molecular Biology
Ines Huebner, Jan-Niklas Dienemann, Julia Friederich, Sabine Schneider, Stephan A. Sieber
ACS CHEMICAL BIOLOGY
(2020)
Article
Multidisciplinary Sciences
Jiqing Du, Marie-Kristin von Wrisberg, Burak Gulen, Matthias Stahl, Christian Pett, Christian Hedberg, Kathrin Lang, Sabine Schneider, Aymelt Itzen
Summary: Legionella pneumophila infects eukaryotic cells by modifying the activity of Rab1 protein through DrrA/SidM protein secretion. A chemical approach was used to study the interaction between Rab1 and DrrA, revealing a non-conventional Rab-binding site. This interaction allosterically activates DrrA, providing insights into Legionella infection mechanism.
NATURE COMMUNICATIONS
(2021)
Article
Chemistry, Multidisciplinary
Cornelia A. Karg, Shuaijun Wang, Nader Al Danaf, Ryan P. Pemberton, Denzil Bernard, Maibritt Kretschmer, Sabine Schneider, Themistoklis Zisis, Angelika M. Vollmar, Don C. Lamb, Stefan Zahler, Simone Moser
Summary: Chlorophyll and heme are essential pigments in life, and their metabolites have important biological activities. Recent studies have shown that phyllobilins, a derivative of chlorophyll, can target actin, a major component of the cytoskeleton, affecting actin dynamics and related processes in cancer cells. This discovery opens up new possibilities for research in plant science, ecology, and physiology.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Review
Biochemistry & Molecular Biology
David Schmidl, Niko S. W. Lindlar ne Jonasson, Annika Menke, Sabine Schneider, Lena J. Daumann
Summary: The activation of molecular oxygen for selective functionalization and repair of DNA and RNA nucleobases is achieved by alpha-ketoglutarate/iron-dependent dioxygenases. This article focuses on the human homologues AlkBH and TET enzymes, discussing the importance of studying enzyme-substrate interactions and turnover for understanding their mode of action. Various analytical methods have been employed to study changes in the active site and overall enzyme structure, and several methods are available to assess enzyme activity. The article aims to provide a comprehensive synopsis for researchers in the field of epigenetic processes and DNA/RNA repair and modification.
Article
Chemistry, Multidisciplinary
Hulya Aldemir, Shuangjie Shu, Francoise Schaefers, Hanna Hong, Rene Richarz, Sabrina Harteis, Manuel Einsiedler, Tobias M. Milzarek, Sabine Schneider, Tobias A. M. Gulder
Summary: The arylomycin antibiotics are potent inhibitors of bacterial type I signal peptidase, containing a biaryl structural motif reminiscent of glycopeptide antibiotics. AryC, a cytochrome P450 enzyme, performs biaryl coupling in arylomycin biosynthesis without the need for any protein interaction partner, due to its strongly hydrophobic cavity at the surface pointing to the substrate tunnel. This unique reactivity enables chemo-enzymatic assembly of arylomycin A2 combining liquid- and solid-phase peptide synthesis advantages.
CHEMISTRY-A EUROPEAN JOURNAL
(2022)
Article
Biochemical Research Methods
Dmytro Makarov, Andras Telek, Tobias Becker, Marie-Kristin Wrisberg, Sabine Schneider, Pavel Kielkowski
Summary: The identification and quantification of modified peptides are important for understanding the biological function of protein modifications. This study introduces a synthesized tandem mass spectrometry tag for direct peptide-PTM quantification.
JOURNAL OF MASS SPECTROMETRY
(2022)
Article
Biology
Leonhard M. Kick, Marie-Kristin Von Wrisberg, Leander S. Runtsch, Sabine Schneider
Summary: Cas13a is a single-molecule effector of the CRISPR-Cas system that plays a role in bacterial and archaeal defense. It has the ability to cleave target RNAs and bystander RNAs, providing protection to the bacterial population. This study focuses on the Cas13a enzyme from the purple bacteria Rhodobacter capsulatus, and reveals its structural and functional characteristics. The research provides insights into the molecular mechanisms and function of this family of RNA-dependent RNA endonucleases.
COMMUNICATIONS BIOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Franziska R. Traube, Marcel Stern, Annika J. Toelke, Martina Rudelius, Ernesto Mejias-Perez, Nada Raddaoui, Beate M. Kuemmerer, Celine Douat, Filipp Streshnev, Manuel Albanese, Paul R. Wratil, Yasmin Gaertner, Milda Nainyte, Grazia Giorgio, Stylianos Michalakis, Sabine Schneider, Hendrik Streeck, Markus Mueller, Oliver T. Keppler, Thomas Carell
Summary: In this study, chemically stabilized siRNA against SARS-CoV-2 was synthesized and modified with peptides, reducing viral loads and virus-induced cytotoxicity. The siRNA was also able to reduce virus replication and virus-induced apoptosis in 3D mucociliary lung microtissues. The adjustment of siRNA sequence allows rapid adaptation to different variants, and conjugation with receptor ligands via click-chemistry enables the construction of targeted siRNAs for a flexible antiviral defense strategy.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Multidisciplinary Sciences
David Ranava, Christopher M. Scheidler, Martin Pfanzelt, Michaela Fiedler, Stephan A. Sieber, Sabine Schneider, Mee-Ngan F. Yap
Summary: A previously unrecognized binding partner of the hibernation-promoting factor (HPF) in Staphylococcus aureus has been discovered, which is functionally linked to cold adaptation and glucose metabolism.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Dora Balogh, Konstantin Eckel, Christian Fetzer, Stephan A. Sieber
Summary: Listeria monocytogenes has two ClpP isoforms that form a heterooligomeric complex with enhanced proteolytic activity. The formation of this complex is temperature-dependent, with a maximum ratio at 30 degrees C. Knockout strains of ClpP1, ClpP2, and ClpP1/2 were constructed to study their role at elevated temperatures. Whole proteome mass-spectrometry and co-immunoprecipitation analysis revealed that ClpP2 is essential for substrate entry and regulation of proteins, while ClpP1 functions as an enhancer of protein degradation in the heterocomplex. Several putative ClpP2 substrates were identified using an integrated proteomic approach.
RSC CHEMICAL BIOLOGY
(2022)
