Article
Biochemistry & Molecular Biology
Brock Nelson, Nathan Soper, Tania J. Lupoli
Summary: Functional interactions between the molecular chaperone DnaK and cofactor J-proteins are important for proteostasis. Adding C-terminal tags to N-terminal J-domain truncations of mycobacterial DnaJ1 and DnaJ2 promotes additional interactions with DnaK. These C-terminally modified J-domains suppress chaperone activity in mycobacterial cells and can be used to study chaperone-cofactor interactions in other organisms.
Article
Biochemistry & Molecular Biology
Bruno Fauvet, Andrija Finka, Marie-Pierre Castanie-Cornet, Anne-Marie Cirinesi, Pierre Genevaux, Manfredo Quadroni, Pierre Goloubinoff
Summary: This study investigated the collaboration between Hsp90 and Hsp70 in bacteria through comparative proteomic analysis, revealing that bacterial Hsp90 may mediate the degradation of aggregation-prone Hsp70-Hsp40 substrates possibly through the HslUV protease. It was found that the triple mutant Delta KJG showed higher levels of metabolic and respiratory enzymes compared to Delta KJ, indicating a role of Hsp90 in protein homeostasis in bacteria.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Shaikha Y. Almaazmi, Rupinder P. Kaur, Harpreet Singh, Gregory L. Blatch
Summary: Cellular proteostasis relies on a network of molecular chaperones and co-chaperones, which regulate the folding and degradation of proteins. The J domain protein (JDP) family plays a crucial role in the formation of a protein quality control network. In malaria parasites, JDPs are exported into infected erythrocytes and may enhance the chaperone power needed for survival and pathogenesis. The interactions between exported JDPs, malarial Hsp70, and human Hsp70 are important for the trafficking of virulence factors and proteostasis of protein complexes associated with pathology.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2023)
Article
Microbiology
Allison Fay, John Philip, Priya Saha, Ronald C. Hendrickson, Michael S. Glickman, Kristin Burns-Huang
Summary: This study reveals that chaperones like DnaK support antimicrobial resistance in mycobacteria, including Mycobacterium tuberculosis, by stabilizing resistance-conferring amino acid substitutions in drug targets. Specifically, the DnaK system associates more with AMR-conferring mutant RNA polymerase and helps counter the stress imposed by these substitutions, highlighting chaperones as potential targets for combating AMR in mycobacteria and other pathogens.
Review
Biochemistry & Molecular Biology
Shaikha Y. Almaazmi, Harpreet Singh, Tanima Dutta, Gregory L. Blatch
Summary: The heat shock protein 40 (Hsp40) family, also known as J domain proteins (JDPs), regulates the function of their Hsp70 partners by ensuring the right substrate engagement at the right time and location within the cell. The human malaria parasite, Plasmodium falciparum, has a large number of JDPs (PfJDPs) in its genome, with a significant proportion of these exported into the host cell during the asexual stage of the life cycle. These exported PfJDPs have been found to play a crucial role in the survival and pathogenesis of the malaria parasite by interacting with both host and parasite Hsp70s.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Review
Neurosciences
Joao Vasco Ferreira, Ana da Rosa Soares, Paulo Pereira
Summary: Aging is associated with the accumulation of proteotoxic material inside cells, which may contribute to neurodegenerative diseases such as Alzheimer's and Parkinson's. Despite efforts to develop therapies targeting proteotoxic accumulation, progress has been limited, as evidenced by the failure of clinical trials for Alzheimer's disease treatments. It is increasingly recognized that regulation of proteostasis involves complex transcellular networks and may shed new light on aging and disease mechanisms.
FRONTIERS IN NEUROSCIENCE
(2022)
Article
Oncology
Sara Maria Ayala Mariscal, Janine Kirstein
Summary: The functional network of HSP70 chaperones, JDPs, and NEF can prevent and reverse protein aggregation associated with neurodegenerative diseases. JDPs play a crucial role in selecting specific substrates and remodeling their structure, making them an attractive target for pharmacological intervention in neurodegenerative diseases.
EXPERIMENTAL CELL RESEARCH
(2021)
Review
Biochemistry & Molecular Biology
Barbara Tedesco, Veronica Ferrari, Marta Cozzi, Marta Chierichetti, Elena Casarotto, Paola Pramaggiore, Francesco Mina, Mariarita Galbiati, Paola Rusmini, Valeria Crippa, Riccardo Cristofani, Angelo Poletti
Summary: Motoneuron diseases (MNDs) are neurodegenerative conditions associated with death of upper and/or lower motoneurons (MNs). Protein misfolding and defects in the protein quality control system are key factors in MND pathogenesis. Heat Shock Protein 70 (HSP70) and small heat shock proteins (sHSPs/HSPBs) play important roles in maintaining proteostasis and protecting against proteotoxicity in MNDs. Understanding the role of HSPBs in MNDs may provide insights for developing therapeutic strategies.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Biochemistry & Molecular Biology
Bruno Fauvet, Mathieu E. Rebeaud, Satyam Tiwari, Paolo De Los Rios, Pierre Goloubinoff
Summary: Life is a non-equilibrium phenomenon, where proteins fold and structure according to thermodynamic principles. Cells have evolved molecular chaperones to counteract protein misfolding and maintain structural stability.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Francoise A. Dekker, Stefan G. D. Rudiger
Summary: This article discusses the molecular mechanism and cellular function of TRAP1, and explores possible links to Alzheimer's Disease (AD). TRAP1, as a member of the Hsp90 family, plays a crucial role in chaperoning essential cellular proteins despite not being regulated by co-chaperones like its cytosolic counterparts. It is also involved in maintaining mitochondrial integrity by regulating mitochondrial pore opening through Cyclophilin D.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Article
Microbiology
Nikita Mangla, Ramandeep Singh, Nisheeth Agarwal
Summary: M. tuberculosis is exposed to various extracellular stressful conditions and has mechanisms to endure and adapt to survive. mHtpG, in association with DnaJ2 cochaperone, assists the mycobacterial DnaK/DnaJ/GrpE chaperone system, suggesting its potential role in stress management of the pathogen.
MICROBIOLOGY SPECTRUM
(2023)
Article
Multidisciplinary Sciences
Jack Llewellyn, Venkatesh Mallikarjun, Ellen Appleton, Maria Osipova, Hamish T. J. Gilbert, Stephen M. Richardson, Simon J. Hubbard, Joe Swift
Summary: Cells respond to stress by producing chaperone proteins to maintain protein function, but aging leads to a disruption of protein balance and the formation of disease-related protein aggregates. Understanding the molecular causes of this proteostasis deterioration is important for disease interventions and cell health maintenance in regenerative medicine strategies.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Bakul Piplani, C. M. Santosh Kumar, Peter A. Lund, Tapan K. Chaudhuri
Summary: Mycobacterium tuberculosis encodes two chaperonin proteins, MtbCpn60.1 and MtbCpn60.2, which have sequence similarity with E. coli chaperonin GroEL. Both MtbCpn60.1 and MtbCpn60.2 assist the folding of certain chaperonin clients, but only MtbCpn60.2 can fully rescue GroEL-depleted E. coli cells. MtbCpn60.1 has limited ability to support cell growth and proliferation and assist the folding of certain clients. The differences between MtbCpn60.1 and MtbCpn60.2 may be due to their intrinsic sequence features.
MOLECULAR MICROBIOLOGY
(2023)
Review
Cell Biology
Christian Muench, Janine Kirstein
Summary: Protein quality control pathways are essential for maintaining a functional proteome and preventing diseases such as Alzheimer's and Parkinson's. The EMBO workshop on protein quality control covered various aspects of this field, including the underlying mechanisms and medical implications. This report summarizes the workshop and highlights selected presentations.
CELL STRESS & CHAPERONES
(2023)
Article
Multidisciplinary Sciences
Hubert Wyszkowski, Anna Janta, Wiktoria Sztangierska, Igor Obuchowski, Tomasz Chamera, Agnieszka Klosowska, Krzysztof Liberek
Summary: The study investigates the functional differences between two classes of JDPs in yeast during the process of protein disaggregation, highlighting the superior aggregate binding ability of Ydj1 and the recruitment of more Ssa1 molecules to substrates by Sis1, which depends on its specific binding mechanism with Hsp70. These findings suggest that the subspecialization of JDPs during protein reactivation improves the robustness and efficiency of the disaggregation machinery.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Chemistry, Multidisciplinary
Brian F. Fisher, Seong Ho Hong, Samuel H. Gellman
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2017)
Article
Chemistry, Multidisciplinary
Brian F. Fisher, Seong Ho Hong, Samuel H. Gellman
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2018)
Article
Chemistry, Multidisciplinary
Michael G. Wuo, Seong Ho Hong, Arunima Singh, Paramjit S. Arora
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2018)
Article
Chemistry, Medicinal
Krishna Kumar, Tania J. Lupoli
ACS MEDICINAL CHEMISTRY LETTERS
(2020)
Article
Multidisciplinary Sciences
Seong Ho Hong, Daniel Y. Yoo, Louis Conway, Khyle C. Richards-Corke, Christopher G. Parker, Paramjit S. Arora
Summary: An aberrant Ras signaling pathway is linked to hyper proliferative diseases, with Ras being a key focus of drug discovery efforts. The study constructed a synthetic Sos protein mimic that interacts with Ras and modulates downstream kinase signaling. This proteomimetic shows selective toxicity to cancer cells with upregulated macropinocytosis and oncogenic Ras mutations.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Chemistry, Medicinal
Meng Zheng, Tania J. Lupoli
Summary: The study shows that modulation of Arr can activate rifamycin modification in mycobacteria, and a PARP inhibitor can sensitize M. smegmatis to rifampin by inhibiting Arr. The combination treatment is effective in inhibiting growth of multidrug-resistant Mycobacterium abscessus.
ACS INFECTIOUS DISEASES
(2021)
Review
Biochemistry & Molecular Biology
Meng Zheng, Maggie Zheng, Samuel Epstein, Alexa P. Harnagel, Hanee Kim, Tania J. Lupoli
Summary: This article summarizes recent advances in chemical biology tools for modulating O-antigen synthesis and composition in bacterial cells, as well as detecting unique glycan sequences. It also discusses the biochemistry and structural biology of O-antigen biosynthetic machinery, providing guidance for designing novel chemical and biomolecular probes to investigate the complex sugar architecture of Gram-negative cells.
ACS CHEMICAL BIOLOGY
(2021)
Article
Chemistry, Medicinal
Maggie Zheng, Meng Zheng, Tania J. Lupoli
Summary: Research has shown that rational mutations in the allosteric site of the nucleotidyltransferase RmlA can lead to expanded substrate tolerance and improvements in catalytic activity, which can be explained by subtle changes in quaternary structure and interactions with ligands.
ACS INFECTIOUS DISEASES
(2022)
Article
Chemistry, Multidisciplinary
Meng Zheng, Maggie C. Zheng, Hanee Kim, Tania J. Lupoli
Summary: Bacterial glycomes contain prokaryote-specific or rare sugars that are not present in mammals. The nucleotidyltransferase RmlA in bacteria initiates the production of rare NDP-sugars, which regulate glycan assembly through feedback inhibition of RmlA. Limited access to rare NDP-sugars hampers the study of bacterial glycan biosynthesis. By using synthetic rare NDP-sugars, this study identifies the structural features required for regulation of RmlA and provides new routes to access rare sugar substrates.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Multidisciplinary
Alexa P. Harnagel, Mia Sheshova, Meng Zheng, Maggie Zheng, Karolina Skorupinska-Tudek, Ewa Swiezewska, Tania J. Lupoli
Summary: Bacteria synthesize unique sugars, such as l-rhamnose, that are essential for bacterial glycans involved in survival or host infection. Rhamnosyltransferases (RTs) are responsible for incorporating l-rhamnose into glycans. Inhibition of RTs could be a novel strategy to prevent bacterial infections.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Medicinal
Maggie Zheng, Meng Zheng, Tania J. Lupoli
Summary: Rational mutations in the allosteric site of the nucleotidyltransferase RmlA lead to expanded substrate tolerance and improvements in catalytic activity. These observations will help inform future studies on the directed biosynthesis of diverse bacterial glycoconjugates.
ACS INFECTIOUS DISEASES
(2022)
Article
Biochemical Research Methods
Aweon Richards, Gideon K. Yawson, Brock Nelson, Tania J. Lupoli
Summary: This article introduces an experimental toolbox for evaluating inhibitors against the mycobacterial DnaK chaperone network, including a coupled-enzymatic assay, a proteolytic cleavage assay, and a protein renaturation assay.