Article
Multidisciplinary Sciences
Arjun Saha, Arieh Warshel
Summary: This study explored the molecular basis of substrate translocation by the AAA+ motor of the 26S proteasome using simulation approaches, revealing the role of electrostatic interactions and validating the involvement of bulkier residues in pore loop 1 in substrate translocation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Biochemistry & Molecular Biology
Taylor Thomas, David Salcedo-Tacuma, David M. Smith
Summary: This review discusses the regulation of proteasomes, with a focus on the unique characteristics of the 11S, REGs, or PA26/PA28 family of regulators. The evolution and cellular biology of these regulators are explored, and their structure and function are comprehensively compared, highlighting unanswered questions regarding their regulatory mechanisms and broader roles in proteostasis.
Article
Cell Biology
Kartikeya Vijayasimha, Marilyn Vo Tran, Amy L. Leestemaker-Palmer, Brian P. Dolan
Summary: The study demonstrates that fusion of NEDD8 to a protein of interest leads to rapid degradation, depending on functional ubiquitin-conjugation system. However, the inhibitor of the E1 activating enzyme for NEDD8 failed to prevent degradation of other destabilized substrates.
Article
Multidisciplinary Sciences
Afu Fu, Victoria Cohen-Kaplan, Noa Avni, Ido Livneh, Aaron Ciechanover
Summary: The degradation of proteins through the ubiquitin-proteasome system is a complex multistep process that relies on the coordinated activity of various enzymes. Nuclear condensates containing essential components like p62 play a crucial role in protein quality control and degradation, especially under stress conditions. These assemblies, generated through liquid-liquid phase separation, efficiently facilitate proteolysis of nuclear proteins and unassembled proteasome subunits, indicating their involvement in cellular protein quality control.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Biochemistry & Molecular Biology
Hangjun Sun, Xinxin Jing, Chaonan Wang, Pengyue Wang, Ziting Huang, Bingjian Sun, Pengbai Li, Honglian Li, Chao Zhang
Summary: Plant viruses cause significant damage to global crop production and plants activate defense signaling pathways to hinder virus propagation. Protein homeostasis regulation plays a vital role in the ongoing battle between plants and viruses.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Abramo J. Manfredonia, Daniel A. Kraut
Summary: The ubiquitin-proteasome system is responsible for protein degradation in eukaryotic cells. The study showed that degradation of ubiquitin-independent degrons (UbIDs) is slower and relies on loosely folded substrates. Furthermore, UbID degradation is ATP-independent.
Review
Biochemistry & Molecular Biology
Gili Ben-Nissan, Naama Katzir, Maria Gabriella Fuzesi-Levi, Michal Sharon
Summary: Proteasomes, traditionally considered intracellular complexes responsible for maintaining proteostasis, have also been found in extracellular body fluids, indicating a regulated physiological process. Studies have shown the presence of 20S proteasome subunits in at least 25 different body fluids, with the dominant proteasome activator being the PA28 alpha/beta complex. Positive correlations have been observed between 20S proteasome levels and disease severity or treatment efficacy in plasma and extracellular vesicles, suggesting the involvement of this complex in pathophysiology. Considerations and practical experimental methods for investigating extracellular proteasomes are also discussed.
Review
Biochemistry & Molecular Biology
Vandita Dwivedi, Karina Yaniv, Michal Sharon
Summary: Evidence from clinical studies show that functional 20S proteasome complexes circulate in plasma, with elevated levels in patients with various diseases. The levels of circulating c20S correlate positively with treatment efficacy and survival rates, indicating a potential role in pathophysiology.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2021)
Article
Biochemistry & Molecular Biology
Destini A. Stanton, Emily A. Ellis, Mariah R. Cruse, Rafael Jedlinski, Daniel A. Kraut
Summary: The 26S proteasome is responsible for the unfolding and degradation of intracellular proteins in eukaryotes. The ATPase ring of the proteasome grabs onto substrates, unfolds them, and translocates them into the degradation chamber. The aromatic paddle motif in each ATPase subunit plays an important role in the proteasome's ability to unfold and translocate substrates.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2023)
Review
Cell Biology
Michael Basler, Marcus Groettrup
Summary: The immunoproteasome is a special type of proteasome induced under inflammatory conditions, contributing to protein homeostasis in cells and involved in immune response, T cell expansion, and inflammatory diseases. Targeting the immunoproteasome has shown therapeutic effectiveness in cancer, autoimmune diseases, and transplantation in preclinical animal models.
Article
Chemistry, Multidisciplinary
Frances P. Rodriguez-Rivera, Samuel M. Levi
Summary: Small molecule degraders have the potential to catalytically destroy target proteins at substoichiometric concentrations, lowering administered doses and extending pharmacological effects. However, a holistic framework that evaluates different degradation modes from a catalytic perspective is currently lacking.
ACS CENTRAL SCIENCE
(2021)
Review
Biochemistry & Molecular Biology
Dare E. George, Jetze J. Tepe
Summary: The proteasome system is crucial for protein degradation, and dysfunction can lead to various diseases. Enhancing proteasome-mediated protein degradation with small molecules may be a valuable strategy for treating neurodegenerative diseases.
Article
Biology
Hudson W. Coates, Isabelle M. Capell-Hattam, Ellen M. Olzomer, Ximing Du, Rhonda Farrell, Hongyuan Yang, Frances L. Byrne, Andrew J. Brown
Summary: Cholesterol synthesis is an energy- and oxygen-intensive process, but the regulatory effects of hypoxia on pathway enzymes are not well understood. Researchers have discovered that hypoxia triggers the truncation of the rate-limiting enzyme squalene monooxygenase (SM), allowing it to maintain activity and pathway flux. This mechanism involves increased proteasomal degradation of SM and accumulation of its substrate squalene. These findings provide insights into how SM accommodates fluctuating substrate levels and may contribute to its oncogenic properties.
Review
Pharmacology & Pharmacy
Alastair C. Keen, Manuela Jorg, Michelle L. L. Halls
Summary: The ubiquitin-proteasome system is a major pathway for protein degradation in cells, and methods have been developed to exploit this system for targeted protein degradation. Targeted protein degraders have been useful tools in discovery research and are being developed as therapeutics. However, most targeted protein degrader technologies have been developed for cytosolic proteins, while examples for G protein-coupled receptor (GPCR) degradation are limited. This review discusses the strategies used for applying targeted protein degradation to GPCRs and explores alternative approaches used for degrading other integral membrane proteins.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Saskia Roedl, Johannes M. Herrmann
Summary: Protein abundance is regulated by synthesis and degradation rates, and the proteasome is the major machinery for protein degradation in eukaryotic cells. Recent studies have revealed the important role of the proteasome in mitochondrial protein quality control, removing damaged proteins from the mitochondria and maintaining protein homeostasis. This review provides an overview of the components and functions involved in proteasomal degradation of mitochondrial proteins in Saccharomyces cerevisiae, highlighting the dynamic adaptation of protein levels in response to specific conditions.
Article
Microbiology
Hyewon Byun, Poulami Das, Houqing Yu, Alejandro Aleman, Mary M. Lozano, Andreas Matouschek, Jaquelin P. Dudley
Article
Biochemistry & Molecular Biology
Tomonao Inobe, Masayuki Tsukamoto, Miyuki Nozaki
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2018)
Article
Multidisciplinary Sciences
Gen Matsumoto, Tomonao Inobe, Takanori Amano, Kiyohito Murai, Nobuyuki Nukina, Nozomu Mori
SCIENTIFIC REPORTS
(2018)
Review
Biochemistry & Molecular Biology
Takuya Tomita, Andreas Matouschek
Article
Multidisciplinary Sciences
J. P. Renn, S. Bhattacharyya, H. Bai, C. He, H. Li, A. F. Oberhauser, J. F. Marko, D. E. Makarov, A. Matouschek
SCIENTIFIC REPORTS
(2019)
Article
Multidisciplinary Sciences
Kirby Martinez-Fonts, Caroline Davis, Takuya Tomita, Suzanne Elsasser, Andrew R. Nager, Yuan Shi, Daniel Finley, Andreas Matouschek
NATURE COMMUNICATIONS
(2020)
Article
Multidisciplinary Sciences
Takuya Tomita, Jon M. Huibregtse, Andreas Matouschek
NATURE COMMUNICATIONS
(2020)
Article
Biochemical Research Methods
Bingqing Zhao, Colin P. Reilly, Caroline Davis, Andreas Matouschek, James P. Reilly
JOURNAL OF PROTEOME RESEARCH
(2020)
Article
Biochemistry & Molecular Biology
Caroline Davis, Brian Logan Spaller, Andreas Matouschek
Summary: The majority of regulated protein degradation in eukaryotes is carried out by the 26S proteasome, which targets proteins for degradation through ubiquitination at disordered regions. Recent studies have uncovered the intricate mechanisms of substrate recognition by the proteasome, highlighting the importance of diverse ubiquitin chains, unique ubiquitin receptors, and initiation region modifications in protein degradation.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2021)
Article
Cell Biology
Ramhari Kumbhar, Anthony Sanchez, Jullian Perren, Fade Gong, David Corujo, Frank Medina, Sravan K. Devanathan, Blerta Xhemalce, Andreas Matouschek, Marcus Buschbeck, Bethany A. Buck-Koehntop, Kyle M. Miller
Summary: This study uncovers the crucial factors involved in the recognition of DNA lesion sites by the histone demethylase KDM5A, including a noncanonical poly(ADP-ribose) binding region and the histone variant macroH2A1.2. These factors are essential for KDM5A's functions at DNA damage sites and play key roles in DNA repair processes.
JOURNAL OF CELL BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Amit Kumar Singh Gautam, Houqing Yu, Christopher Yellman, Adrian H. Elcock, Andreas Matouschek
Summary: The proteasome is a powerful intracellular protease that can degrade any protein, self or foreign, through ubiquitin tagging. It consists of approximately 33 subunits, and their assembly and activity are regulated by post-translational modifications on long disordered regions of the subunits. Molecular modeling and biochemical experiments have shown that some disordered regions of proteasome subunits access the substrate recognition sites and are constructed from amino acid sequences that escape recognition.
Article
Infectious Diseases
Darlene Bhavnani, Emily R. James, Kaitlyn E. Johnson, Sylvie Beaudenon-Huibregtse, Patrick Chang, Paul J. Rathouz, Minda Weldon, Andreas Matouschek, Amy E. Young
Summary: This study investigated the relationship between viral load and the risk of SARS-CoV-2 transmission to contacts. It found that higher viral load was associated with an increased risk of transmission to close contacts. Even asymptomatically or pre-symptomatically infected cases had a significant risk of transmitting the virus to contacts. These findings suggest that viral load plays an important role in virus transmission.
BMC INFECTIOUS DISEASES
(2022)
Article
Chemistry, Physical
Lucas W. Henderson, Edie M. Sharon, Amit K. S. Gautam, Adam J. Anthony, Martin F. Jarrold, David H. Russell, Andreas Matouschek, David E. Clemmer
Summary: Mass spectrometry studies show that the stability of S. cerevisiae 20S proteasome undergoes related configurations and transitions during temperature changes, possibly linked to the opening of the proteolytic core. The study indicates that the proteasome remains intact and all transitions are reversible. Three types of structures are identified based on thermodynamic analysis: energetically stabilized closed configurations, high-entropy precursor states, and open pore structures. Opening of the 20S pore in the absence of the regulatory unit involves a charge-priming process. However, only a small fraction of precursor configurations actually open to expose the catalytic cavity.
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
(2023)
Article
Chemistry, Analytical
Adam J. Anthony, Amit K. S. Gautam, Lohra M. Miller, Yiran Ma, Anya G. Hardwick, Anu Sharma, Subhadip Ghatak, Andreas Matouschek, Martin F. Jarrold, David E. Clemmer
Summary: Charge detection mass spectrometry (CDMS) was used to study proteasomes and their oligomers. Mass measurements of 20S, 19S, 26S, and 30S proteasomes from Saccharomyces cerevisiae were conducted, and larger assemblies (20S)(x) and (19S)(x) were observed under certain conditions. The findings contribute to a better understanding of proteasomes and their oligomeric states.
ANALYTICAL CHEMISTRY
(2023)
Article
Chemistry, Analytical
Adam J. Anthony, Amit K. S. Gautam, Lohra M. Miller, Yiran Ma, Anya G. Hardwick, Anu Sharma, Subhadip Ghatak, Andreas Matouschek, Martin F. Jarrold, David E. Clemmer
Summary: This study examined the use of Charge Detection Mass Spectrometry (CDMS) to study proteasomes. The masses of different proteasomes were measured and larger assemblies were observed under certain conditions. The study also discussed possible structures for the formation of these assemblies and the utility of CDMS in characterizing proteasomes and related oligomers.
ANALYTICAL CHEMISTRY
(2023)