Review
Biochemistry & Molecular Biology
Chen Jiang, Max Wynne, Damon Huber
Summary: The Sec machinery in bacteria is responsible for transporting proteins across the cytoplasmic membrane, requiring the substrates to be in an unfolded conformation. To prevent folding in the cytoplasm, bacteria have evolved a complex quality control network consisting of three branches: avoidance of cytoplasmic intermediates, inhibition of folding Sec substrate proteins, and destruction of potential translocation inhibitors. Stress response pathways also help restore protein-folding homeostasis when environmental conditions inhibit translocation.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Kamilla Gomori, Melissa Herwig, Roua Hassoun, Heidi Budde, Nusratul Mostafi, Simin Delalat, Suvasini Modi, Merima Begovic, Tamara Szabados, Judit Pipis, Nikolett Farkas-Morvay, Istvan Lepran, Arpad Kovacs, Andreas Mugge, Peter Ferdinandy, Aniko Gorbe, Peter Bencsik, Nazha Hamdani
Summary: This study investigates the effects of volume overload on the heart using a rat model and finds that it leads to cardiac hypertrophy, mechanical dysfunction, dysregulated signaling pathways, and increased oxidative stress. Furthermore, oxidative stress causes impairment of the protein quality control system.
Article
Cardiac & Cardiovascular Systems
Roua Hassoun, Heidi Budde, Saltanat Zhazykbayeva, Melissa Herwig, Marcel Sieme, Simin Delalat, Nusratul Mostafi, Kamilla Goemoeri, Melina Tangos, Muhammad Jarkas, Steffen Pabel, Stefanie Bruckmueller, Marina Skrygan, Maria Lodi, Kornelia Jaquet, Vasco Sequeira, Thilo Gambichler, Cris Dos Remedios, Arpad Kovacs, Hans Georg Mannherz, Andreas Muegge, Samuel Sossalla, Nazha Hamdani
Summary: Hypertrophic cardiomyopathy is a complex myocardial disorder with characteristics of increased stiffness in cardiomyocytes from patients, with titin abnormalities and oxidative stress playing significant roles. The study suggests that reducing oxidative stress may be a viable therapeutic approach to attenuating cardiac dysfunction in heart failure and HCM.
INTERNATIONAL JOURNAL OF CARDIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Elena B. Tikhonova, Sneider Alexander Gutierrez Guarnizo, Morgana K. Kellogg, Alexander Karamyshev, Igor M. Dozmorov, Zemfira N. Karamysheva, Andrey L. Karamyshev
Summary: Regulation of Aberrant Protein Production (RAPP) is a protein quality control mechanism in mammalian cells. It degrades the mRNA of nascent proteins that cannot associate with their natural interacting partners. Depletion of human SRP54, an SRP subunit, triggers RAPP and leads to decreased expression of mRNAs encoding secretory and membrane proteins. The loss of SRP54 also results in the upregulation of a specific network of HSP70/40/90 chaperones, increased ribosome-associated ubiquitination, and changes in the expression of RPS27 and RPS27L, indicating ribosome rearrangement.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Review
Plant Sciences
Hyoung Yool Lee, Ok Jin Hwang, Kyoungwhan Back
Summary: Melatonin is crucial for maintaining steady-state protein levels in plants and is involved in regulating protein quality control via the chaperone network, autophagy, and ubiquitin-proteasome systems. Its physiological effects are attributed to potent antioxidant activity and signaling molecule functions in inducing a variety of melatonin-mediated genes. Melatonin plays a pivotal role as a signaling molecule in protein quality control and stress tolerance in plants, through the coordination of chaperone proteins, autophagy processes, and up-regulation of stress-induced transcription factors.
JOURNAL OF EXPERIMENTAL BOTANY
(2022)
Article
Plant Sciences
Parthompong Ves-urai, Sucheewin Krobthong, Karnpitcha Thongsuk, Sittiruk Roytrakul, Chotika Yokthongwattana
Summary: Secretome analysis of a salt-tolerant and control Chlamydomonas reinhardtii revealed 514 differentially expressed proteins. Proteins involved in membrane transport and trafficking, signal transduction, and channel proteins were up-regulated in the salt-tolerant secretome, indicating that the response to saline stress affects both intracellular and extracellular proteins. Additionally, a high proportion of predicted secreted proteins lacked a signal peptide, suggesting potential unconventional protein secretion pathways.
Review
Biochemistry & Molecular Biology
Yunting Fu, Xifeng Li, Baofang Fan, Cheng Zhu, Zhixiang Chen
Summary: Maintaining functional protein homeostasis in chloroplasts is crucial for plant fitness and survival. Research has uncovered various mechanisms involved in chloroplast protein quality control and turnover, such as endosymbiotically-derived proteases, ubiquitin-dependent turnover, chloroplast-associated degradation, chloroplast unfolded protein response, and vesicle-mediated degradation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biotechnology & Applied Microbiology
Masashi Yoshida, Sae Kato, Shizu Fukuda, Shingo Izawa
Summary: The study found that pretreatment with mild ethanol upregulated the expression of proteins involved in PQC and mitigated the accumulation of insoluble proteins, even under severe ethanol stress. These results provide novel insights into ethanol tolerance and the adaptive capacity of yeast cells, especially during the brewing process.
APPLIED AND ENVIRONMENTAL MICROBIOLOGY
(2021)
Review
Chemistry, Medicinal
Jiangnan Zhang, Wenliang Qiao, Youfu Luo
Summary: Mitochondrial quality control proteases play a crucial role in maintaining mitochondrial function, regulating cell development, and modulating cancer therapy. They degrade misfolded proteins, regulate mitochondrial morphology, and serve as promising targets for novel antitumor drugs.
MEDICINAL RESEARCH REVIEWS
(2023)
Review
Physiology
Sebastian Koetter, Martina Krueger
Summary: This review explores the composition of the sarcomere, the smallest molecular unit of muscle contraction and relaxation, and focuses on the role of the sarcomere protein titin and its relationship with protein quality control. It summarizes the current state of research on titin turnover and discusses the involvement of various intracellular degradation mechanisms. Additionally, it examines how perturbations in protein quality control can affect sarcomeric proteins, particularly titin, in different disease states.
FRONTIERS IN PHYSIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Karolina Szczepanowska, Aleksandra Trifunovic
Summary: Mitochondria rely on chaperones and proteases for protein homeostasis, with proteases like LON and ClpXP modulating essential functions beyond quality control. Impaired mitochondrial protease function is linked to various pathological conditions, and recent research has identified them as potential targets for anticancer therapies.
Article
Oncology
Ka-Yiu Edwin Kong, Joao P. L. Coelho, Matthias J. Feige, Anton Khmelinskii
Summary: A healthy and functional proteome is crucial for cell physiology, but errors in protein metabolism and changes in the environment can disrupt proteome homeostasis. Mislocalized and orphan proteins can form due to targeting errors or improper assembly, impacting cellular functions. Quality control mechanisms play a role in minimizing the detrimental effects of these aberrant proteins, which are associated with aging and disease.
EXPERIMENTAL CELL RESEARCH
(2021)
Article
Microbiology
Christopher W. Hamm, Daxton R. Butler, Matthew T. Cabeen
Summary: Bacterial survival depends on appropriate responses to diverse stressors. The environmental model bacterium Bacillus subtilis uses stressosomes to sense environmental stressors and enact the general stress response. Different RsbR paralogs show distinct response magnitude and timing, and can distinguish among stressors.
Article
Physics, Multidisciplinary
Andrew T. R. Christy, Halim Kusumaatmaja, Mark A. Miller
Summary: The presence of inert crowding agents in a three-dimensional environment can significantly enhance or even introduce superselectivity in client molecule-receptor binding. Molecular crowding initially suppresses binding via an entropic penalty, but clients can then more easily form multiple bonds simultaneously.
PHYSICAL REVIEW LETTERS
(2021)
Article
Chemistry, Multidisciplinary
Adrien Marchand, Claire Beauvineau, Marie-Paule Teulade-Fichou, Renato Zenobi
Summary: This study investigated ternary G4:L:P complexes using native mass spectrometry, finding that RHAU preferentially binds to parallel G4s and free external G-quartets. The ligands were observed to prevent peptide binding by direct competition or inducing conformational changes, with Cu-ttpy even increasing peptide binding through a conformational change.
CHEMISTRY-A EUROPEAN JOURNAL
(2021)
Article
Multidisciplinary Sciences
Jennifer Cable, Eilika Weber-Ban, Tim Clausen, Kylie J. Walters, Michal Sharon, Daniel J. Finley, Yangnan Gu, John Hanna, Yue Feng, Sascha Martens, Anne Simonsen, Malene Hansen, Hong Zhang, Jonathan M. Goodwin, Alessio Reggio, Chunmei Chang, Liang Ge, Brenda A. Schulman, Raymond J. Deshaies, Ivan Dikic, J. Wade Harper, Ingrid E. Wertz, Nicolas H. Thoma, Mikolaj Slabicki, Judith Frydman, Ursula Jakob, Della C. David, Eric J. Bennett, Carolyn R. Bertozzi, Richa Sardana, Vinay V. Eapen, Serena Carra
Summary: Targeted protein degradation is essential for cellular function and development. This process involves tightly regulated protein degradation pathways to eliminate misfolded and aggregated proteins, adjust protein levels during cellular differentiation, and selectively eliminate target proteins. Understanding these pathways can provide insights into disease pathology and the development of novel therapeutics.
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Frank Kozielski, Celeste Sele, Vladimir O. Talibov, Jiaqi Lou, Danni Dong, Qian Wang, Xinyue Shi, Maria Nyblom, Annika Rogstam, Tobias Krojer, Zoe Fisher, Wolfgang Knecht
Summary: The emergence of SARS-CoV-2 in 2019 has posed a serious threat to our health, social and economic systems, leading to the urgent need for new drugs targeting SARS-CoV-2. Research has identified ligands targeting nsp10 as starting points for the development of more potent drugs.
RSC CHEMICAL BIOLOGY
(2022)
Article
Chemistry, Medicinal
Paige M. E. Hawkins, David M. Hoi, Chen-Yi Cheung, Trixie Wang, Diana Quan, Vishnu Mini Sasi, Dennis Y. Liu, Roger G. Linington, Colin J. Jackson, Stefan H. Oehlers, Gregory M. Cook, Warwick J. Britton, Tim Clausen, Richard J. Payne
Summary: Lead analogues of Ohmyungsamycin A and ecumicin were synthesized using solid-phase synthesis and macrolactamization strategy, and showed potent activity against Mtb. These analogues were found to inhibit protein degradation and enhance ATPase activity, and exhibited rapid bactericidal killing activity against Mtb in vitro and in vivo.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemical Research Methods
Sandra Romero-Molina, Yasser B. Ruiz-Blanco, Joel Mieres-Perez, Mirja Harms, Jan Muench, Michael Ehrmann, Elsa Sanchez-Garcia
Summary: PPI-Affinity is a tool that predicts binding affinity of protein-protein and protein-peptide complexes using support vector machine. The tool's performance was evaluated on four benchmark datasets and tested on mutants of specific structures.
JOURNAL OF PROTEOME RESEARCH
(2022)
Review
Clinical Neurology
Masafumi Ihara, Yumi Yamamoto, Yorito Hattori, Wanyang Liu, Hatasu Kobayashi, Hiroyuki Ishiyama, Takeshi Yoshimoto, Satoru Miyawaki, Tim Clausen, Oh Young Bang, Gary K. Steinberg, Elisabeth Tournier-Lasserve, Akio Koizumi
Summary: Moyamoya disease is a rare cause of stroke, with RNF213 identified as the major susceptibility gene with a complex relationship with environmental and genetic risk factors. Different populations carry different gene variants, explaining the variation in disease prevalence among countries.
Article
Multidisciplinary Sciences
Juliana Rey, Maike Breiden, Vanda Lux, Anika Bluemke, Maike Steindel, Kamilla Ripkens, Bastian Moellers, Kenny Bravo Rodriguez, Prisca Boisguerin, Rudolf Volkmer, Joel Mieres-Perez, Tim Clausen, Elsa Sanchez-Garcia, Michael Ehrmann
Summary: This study reports a novel and reversible mechanism of protease activation, where an inactive protease serves as the activator. This mechanism involves the formation of an allosteric complex between HTRA1 and calpain 2, and exhibits activity only towards specific conformations of substrates. These findings have important implications for understanding protein quality control and potential side effects of drug modulation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Heike Chauvistre, Batool Shannan, Sheena M. Daignault-Mill, Robert J. Ju, Daniel Picard, Stefanie Egetemaier, Renata Varaljai, Christine S. Gibhardt, Antonio Sechi, Farnusch Kaschani, Oliver Keminer, Samantha J. Stehbens, Qin Liu, Xiangfan Yin, Kirujan Jeyakumar, Felix C. E. Vogel, Clemens Krepler, Vito W. Rebecca, Linda Kubat, Smiths S. Lueong, Jan Forster, Susanne Horn, Marc Remke, Michael Ehrmann, Annette Paschen, Juergen C. Becker, Iris Helfrich, Daniel Rauh, Markus Kaiser, Sheraz Gul, Meenhard Herlyn, Ivan Bogeski, Jose Neptuno Rodriguez-Lopez, Nikolas K. Haass, Dirk Schadendorf, Alexander Roesch
Summary: This study demonstrates that maintaining a high expression of KDM5B in slow-cycling melanoma cells can induce their differentiation and cell cycle arrest, thereby limiting tumor plasticity. The study also identifies a chemical agent, Cpd1, that can phenocopy the effect of high KDM5B expression and sensitizes melanoma cells to a specific antifolate prodrug.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Multidisciplinary
Sabrina R. Mackinnon, Gustavo A. Bezerra, Tobias Krojer, Tamas Szommer, Frank von Delft, Paul E. Brennan, Wyatt W. Yue
Summary: The study discovered six low-molecular-weight fragments that bind to different sites on the HAO1 structure, demonstrating their potential as inhibitors of HAO1.
FRONTIERS IN CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Nicholas M. Pearce, Rachael Skyner, Tobias Krojer
Summary: The throughput of macromolecular X-ray crystallography experiments has significantly increased over the last decade due to advancements in X-ray beams, detectors, and automation. This has led to the establishment of dedicated centers for crystal-based fragment screening and the ability to collect hundreds of single-crystal diffraction datasets per day. Crystal structures of proteins with small-molecule ligands are crucial for structure-based drug design, but there has been less focus on software and algorithmic aspects and the impact of new methodologies on established paradigms.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Francesca E. Morreale, Stefan Kleine, Julia Leodolter, Sabryna Junker, David M. Hoi, Stepan Ovchinnikov, Anastasia Okun, Juliane Kley, Robert Kurzbauer, Lukas Junk, Somraj Guha, David Podlesainski, Uli Kazmaier, Guido Boehmelt, Harald Weinstabl, Klaus Rumpel, Volker M. Schmiedel, Markus Hartl, David Haselbach, Anton Meinhart, Markus Kaiser, Tim Clausen
Summary: This study successfully reprogrammed the bacterial protein degradation machinery using small-molecule degraders called BacPROTACs. BacPROTACs not only targeted the substrate receptor but also activated ClpC to unfold protein substrates. The in vivo activity of BacPROTACs was demonstrated in mycobacteria, making it a promising tool for both antibiotic discovery and inducible bacterial protein degradation.
Article
Biochemistry & Molecular Biology
Manfred S. Weiss, Jan Wollenhaupt, Galen J. Correy, James S. Fraser, Andreas Heine, Gerhard Klebe, Tobias Krojer, Marjolein Thunnissen, Nicholas M. Pearce
Summary: Jaskolski et al. analyzed diffraction data sets from fragment-screening group depositions and claimed that these data are problematic. However, we demonstrate that none of the criticisms persist if the data are treated properly.
Article
Biochemistry & Molecular Biology
Lorenzo Picchianti, Victor Sanchez de Medina Hernandez, Ni Zhan, Nicholas A. T. Irwin, Roan Groh, Madlen Stephani, Harald Hornegger, Rebecca Beveridge, Justyna Sawa-Makarska, Thomas Lendl, Nenad Grujic, Christin Naumann, Sascha Martens, Thomas A. Richards, Tim Clausen, Silvia Ramundo, G. Elif Karagoz, Yasin Dagdas
Summary: UFMylation is a crucial covalent modification process that maintains endoplasmic reticulum homeostasis. Stalled translation triggers UFMylation of ER-bound ribosomes, activating C53-mediated autophagy for clearance of toxic polypeptides. The study reveals the ancestral role of sAIMs in UFMylation-dependent fine-tuning of C53-mediated autophagy activation, showing that C53 and sAIMs are conserved across eukaryotes but lost in fungi and certain algal lineages.
Article
Multidisciplinary Sciences
Julian F. Ehrmann, Daniel B. Grabarczyk, Maria Heinke, Luiza Deszcz, Robert Kurzbauer, Otto Hudecz, Alexandra Shulkina, Rebeca Gogova, Anton Meinhart, Gijs A. Versteeg, Tim Clausen
Summary: Inhibitor of apoptosis proteins (IAPs) bind to pro-apoptotic proteases, keeping them inactive and preventing cell death. The atypical ubiquitin ligase BIRC6 is the only essential IAP, additionally functioning as a suppressor of autophagy. Cryo-electron microscopy structures showed that BIRC6 forms a megadalton crescent shape that arcs around a spacious cavity containing receptor sites for client proteins. Multivalent binding of SMAC obstructs client binding, impeding ubiquitination of both autophagy and apoptotic substrates. Based on these data, we discuss how the BIRC6/SMAC complex can act as a stress-induced hub to regulate apoptosis and autophagy drivers.
Article
Biology
Sara Scinicariello, Adrian Soderholm, Markus Schaefer, Alexandra Shulkina, Irene Schwartz, Kathrin Hacker, Rebeca Gogova, Robert Kalis, Kimon Froussios, Valentina Budroni, Annika Bestehorn, Tim Clausen, Pavel Kovarik, Johannes Zuber, Gijs A. Versteeg
Summary: Tristetraprolin (TTP) stability is controlled by factors including lysine-ubiquitination and phosphorylation. The E3 ligase HUWE1 was identified as a regulator of TTP stability, indirectly controlling its phosphorylation. This study provides new insights into the regulation of TTP and its impact on immune response.
