Review
Cell Biology
Marissa E. Dean, Jill L. Johnson
Summary: The Hsp90 molecular chaperone and its cohort of interacting cochaperones are crucial for the function of cellular proteins, with cochaperones playing key roles in regulating Hsp90 activity and client protein interactions. These cochaperones can be grouped based on shared Hsp90 interaction domains, and they vary in client specificity, abundance, and tissue distribution. The presence of specialized cochaperones may provide greater control over Hsp90 activities in different tissues or developmental stages.
CELL STRESS & CHAPERONES
(2021)
Article
Biochemistry & Molecular Biology
Diwei Zheng, Weihai Liu, Wenlin Xie, Guanyu Huang, Qiwei Jiang, Yang Yang, Jiarong Huang, Zihao Xing, Mengling Yuan, Mengning Wei, Yao Li, Junqiang Yin, Jingnan Shen, Zhi Shi
Summary: The study revealed that AHA1 is significantly overexpressed in osteosarcoma, associated with prognosis, and promotes tumor growth and metastasis. AHA1 upregulates metabolic activity to meet cellular energy needs and is positively correlated with IDH1 protein. High IDH1 level is also linked to poor prognosis.
SIGNAL TRANSDUCTION AND TARGETED THERAPY
(2021)
Article
Genetics & Heredity
Rebecca Mercier, Danielle Yama, Paul LaPointe, Jill L. Johnson
Summary: Molecular chaperones, such as Hsp90, play a crucial role in maintaining protein stability and cellular health. Hsp90 facilitates the folding and activation of numerous client proteins through an ATP-dependent pathway. The interaction between Hsp90 and cochaperones, such as Hch1 and Cpr6, tightly regulate Hsp90 function and the conformational changes it undergoes during the folding cycle. Understanding these interactions and conformational changes may lead to new strategies for modulating Hsp90 function.
Article
Cell Biology
Nupur Fangaria, Khushboo Rani, Priyanka Singh, Sandeep Dey, Kota Arun Kumar, Sunanda Bhattacharyya
Summary: This study reveals the importance of nuclear translocation of yHSP90α and its recruitment to the DNA double-strand break end in homologous recombination-mediated DNA repair in yeast. The charged-linker domains of yHSP90α play a critical role in nuclear translocation, and Aha1 may promote the nuclear import of yHSP90α.
MOLECULAR BIOLOGY OF THE CELL
(2022)
Article
Chemistry, Medicinal
Bradley M. Keegan, Kevin C. Catalfano, Monimoy Banerjee, Brian S. J. Blagg
Summary: KU 177 has been found to disrupt interactions between Aha1 and Hsp90, inhibiting P301L tau aggregation. Derivatives of KU 177 have been synthesized, leading to the discovery of a new lead compound that can disrupt Aha1/Hsp90 interactions in cells, providing a new pathway for drug discovery.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Biochemistry & Molecular Biology
Thiago Seraphim, Nardin Nano, Yiu Wing Sunny Cheung, Siripat Aluksanasuwan, Carolina Colleti, Yu-Qian Mao, Vaibhav Bhandari, Gavin Young, Larissa Holl, Sadhna Phanse, Yuliya Gordiyenko, Daniel R. Southworth, Carol Robinson, Visith Thongboonkerd, Lisandra M. Gava, Julio C. Borges, Mohan Babu, Leandro R. S. Barbosa, Carlos H. Ramos, Philipp Kukura, Walid A. Houry
Summary: The R2TP complex, formed by RUVBL1 and RUVBL2 ATPases, associates with PIH1D1 and RPAP3 proteins and plays a role in promoting the formation of macromolecular complexes. RPAP3 is identified as the central subunit of R2TP, linking PIH1D1 and RUVBL1/2. The study provides insights into the structure and function of the R2TP complex.
Article
Biochemistry & Molecular Biology
Dennis M. Bjorklund, R. Marc L. Morgan, Jasmeen Oberoi, Katie L. I. M. Day, Panagiota A. Galliou, Chrisostomos Prodromou
Summary: The study identified the interaction between CDC37 and BRAF and determined the crucial structural elements of CDC37 involved in BRAF recognition. The dimerization of BRAF can inhibit the recognition by CDC37, and the consequences of BRAF mutations on signaling were discussed.
Article
Multidisciplinary Sciences
Bin Huang, Ming Sun, Reyal Hoxie, Judy L. M. Kotler, Larry J. Friedman, Jeff Gelles, Timothy O. Street
Summary: Hsp70 and Hsp90 chaperones play important roles in protein quality control. This study reveals that BiP, a Hsp70 chaperone, acts as a cochaperone to accelerate the closure of Grp94, a Hsp90 chaperone. BiP achieves this by interacting with the middle domain of Grp94. These findings provide insights into the enhanced activity of BiP and Grp94 when working together.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Chemistry, Organic
David Guzman Rios, Miguel A. Romero, Jose A. Gonzalez-Delgado, Jesus F. Arteaga, Uwe Pischel
Summary: The [Ru(bpy)2(Nor)2]2+ complex is an efficient catalyst for the aldol reaction of acetone with activated benzaldehydes in a buffered aqueous solution. The role of the metal as an activator for nornicotine organocatalyst ligands enhances catalytic activity by about 4.5 times compared to free nornicotine. The study provides insights into the synergistic effect of organic catalysts and metals.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Jinyoung Park, Sang Chul Shin, Kyeong Sik Jin, Min Joon Lim, Yeojin Kim, Eunice EunKyeong Kim, Eun Joo Song
Summary: Several reports have highlighted the importance of USP35 in cancer, but little is known about its regulatory mechanism. This study shows that the activity of USP35 is regulated through its structural specificity, and the full activity requires the C-terminal domain and insertion region. USP35 forms a homodimer through its C-terminal domain, which prevents its degradation. CHIP, bound to HSP90, interacts with and ubiquitinates USP35, but auto-deubiquitination attenuates this process. Furthermore, the USP35 dimer is necessary for deubiquitination of the substrate Aurora B and regulation of mitotic progression.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Article
Chemistry, Inorganic & Nuclear
Henrik Beer, Alexander Linke, Jonas Bresien, Grzegorz Mloston, Malgorzata Celeda, Alexander Villinger, Axel Schulz
Summary: Formal addition reactions between the open-shell singlet biradical [P(mu-NTer)](2) (1Ter) and xanthione, thioxanthione, as well as ferrocenyl naphthyl thioketone were studied, leading to the formation of strained [2.1.1]-cage P,S-heterocycles. All addition products were isolated and fully characterized by spectroscopic methods, and reversible cleavage of the xanthenthione-biradical addition product was demonstrated by P-31{H-1} NMR spectroscopy. Calculations showed that ketone adducts have lower thermodynamic stability compared to thioketone adducts.
INORGANIC CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Anna G. Mankovich, Brian C. Freeman
Summary: Heat shock protein 90 (Hsp90), a highly conserved molecular chaperone, not only maintains the stability of metastable proteins, but also plays a crucial role in protein transport. The specific contributions of Hsp90 to protein transport are still not well defined, despite numerous connections with factors involved in this process.
Article
Biochemistry & Molecular Biology
Ku-Feng Lin, Michelle Y. Fry, Shyam M. Saladi, William M. Clemons
Summary: Sgt2 and SGTA serve as entry points for the GET pathway, interacting with TA IMPs to facilitate their insertion into the correct membrane. The flexible and conserved C-terminal domain of Sgt2 is sufficient for client binding, forming a helical hand with a hydrophobic groove for higher affinity interaction with client TMDs. These findings highlight structural similarities between Sgt2 and other TPR-containing cochaperone proteins, such as Sti1.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Xiaochuan Liu, Yen-Yu Yang, Yinsheng Wang
Summary: This study revealed a novel mechanism of HSP90 and Aha1 in regulating the miRNA pathway through promoting the folding of Dicer1 protein and demonstrated that Aha1 modulates this process by acting as an autonomous chaperone and a co-chaperone for HSP90.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Bradley M. Keegan, Brian S. J. Blagg
Summary: Disrupting the interactions between Hsp90 and Aha1 has therapeutic potential for inhibiting Aha1-driven cancer metastasis and tau aggregation. Through split Renilla luciferase assays, withaferin A and gedunin were identified as disruptors of Hsp90/Aha1 interactions, providing insights into the binding regions of gambogic acid and gedunin on Hsp90 homodimers.
ACS CHEMICAL BIOLOGY
(2022)
Review
Chemistry, Multidisciplinary
Umut Gunsel, Franz Hagn
Summary: Membrane proteins play crucial roles in cellular processes, and understanding their structure, binding properties, and functional dynamics is essential. Lipid nanodiscs have advantages for NMR structural investigations of membrane proteins in solution, providing insights into their features.
Article
Biochemistry & Molecular Biology
Chiara Giannone, Maria Rita Chelazzi, Andrea Orsi, Tiziana Anelli, Tuan Nguyen, Johannes Buchner, Roberto Sitia
Summary: Antibodies of the IgM class are secreted as planar polymers, with the formation of non-native intra-subunit disulfide bonds playing a key role in the biogenesis of secretory IgM. This unusual assembly pathway is ensured by the engagement of protein disulfide isomerase ERp44, which promotes polymerization and formation of disulfide linkages. This allows secretory polymers to form without disrupting the function of membrane IgM.
Review
Biochemistry & Molecular Biology
Ramona M. Absmeier, Georg J. Rottenaicher, Hristo L. Svilenov, Pamina Kazman, Johannes Buchner
Summary: Light chain amyloidosis (AL) is a systemic disease characterized by abnormal proliferation of plasma cells and the secretion of mutated antibody light chains (LCs) that form fibrils. These fibrils deposit in various organs, particularly the heart and kidney, impairing their function. The molecular mechanisms underlying the aggregation of mutated LCs into fibrils remain unclear, hindering the development of effective diagnostics and therapies.
Article
Biochemistry & Molecular Biology
Maximilian M. Biebl, Florent Delhommel, Ofrah Faust, Krzysztof M. Zak, Ganesh Agam, Xiaoyan Guo, Moritz Muehlhofer, Vinay Dahiya, Daniela Hillebrand, Grzegorz M. Popowicz, Martin Kampmann, Don C. Lamb, Rina Rosenzweig, Michael Sattler, Johannes Buchner
Summary: In the cytosol of eukaryotic cells, the Hsp70 and Hsp90 chaperone machines work together with NudC to facilitate the maturation process of diverse client proteins. NudC acts as a transfer factor by interacting with Hsp40 and displacing Hsp70, allowing the direct transfer of Hsp40-bound client proteins to Hsp90 for further processing.
Article
Biochemistry & Molecular Biology
Vinay Dahiya, Daniel Andreas Rutz, Patrick Moessmer, Moritz Muehlhofer, Jannis Lawatscheck, Matthias Rief, Johannes Buchner
Summary: This study reveals the crucial role of the co-chaperone Hop in the folding process of stringent clients, facilitating the transfer and folding of clients through its interaction with Hsp70 and Hsp90.
Article
Plant Sciences
Petra Schuhmann, Carina Engstler, Kai Kloepfer, Irene L. Guegel, Amine Abbadi, Felix Dreyer, Gunhild Leckband, Bettina Boelter, Franz Hagn, Juergen Soll, Chris Carrie
Summary: The Tic40 gene has been identified as the restorer gene for the MSL system, and heat treatment is hypothesized to restore fertility by inducing a developmental slow down in the cell cycle. The results of this study have important implications for breeding thermotolerant fertile plants using the MSL system.
JOURNAL OF EXPERIMENTAL BOTANY
(2022)
Article
Multidisciplinary Sciences
Patrick Moessmer, Thomas Suren, Ulrike Majdic, Vinay Dahiya, Daniel Rutz, Johannes Buchner, Matthias Rief
Summary: In this study, the interaction between the glucocorticoid receptor and the molecular chaperone system was observed using single-molecule force spectroscopy. The results show that the molecular chaperones can unfold the receptor in a stepwise manner through ATP hydrolysis. These findings provide important insights into the regulation of the glucocorticoid receptor by molecular chaperones.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biotechnology & Applied Microbiology
Patrick Opdensteinen, Laura E. Sperl, Mariam Mohamadi, Nicole Kuendgen-Redding, Franz Hagn, Johannes Felix Buyel
Summary: Nuclear magnetic resonance (NMR) spectroscopy is used to study protein structure and interactions, but requires stable isotope labelling. Traditional labelling methods in E. coli are not suitable for complex proteins. Research shows that cultivating tobacco cell lines in media supplemented with isotope-labelled substrates can efficiently produce labelled proteins for NMR analysis.
PLANT BIOTECHNOLOGY JOURNAL
(2022)
Article
Biology
Layla Drwesh, Benjamin Heim, Max Graf, Linda Kehr, Lea Hansen-Palmus, Mirita Franz-Wachtel, Boris Macek, Hubert Kalbacher, Johannes Buchner, Doron Rapaport
Summary: This study reconstituted the early cytosolic steps of signal-anchored (SA) protein biogenesis and identified molecular (co)chaperones, including Hsp70, Hsp90, and Hsp40 family co-chaperones, that interact with newly synthesized SA proteins. These interactions are mediated by the hydrophobic transmembrane segments of the SA proteins. The study also demonstrated the inhibitory effect of interfering with these interactions on SA protein biogenesis and successfully reconstituted the transfer of peptides from Hsp70 chaperone to the mitochondrial Tom70 receptor in vitro.
Article
Biochemistry & Molecular Biology
Melina Daniilidis, Matthias J. Brandl, Franz Hagn
Summary: Membrane mimetics play a crucial role in studying the structure and function of membrane proteins. In this study, the authors compared the biophysical properties of circularized and linear nanodiscs and found that circularized nanodiscs have improved membrane fluidity and size stability, making them advantageous for high-resolution NMR studies at elevated temperatures.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Biology
Hristo L. Svilenov, Romina Bester, Julia Sacherl, Ramona Absmeier, Carsten Peters, Ulrike Protzer, Carsten Brockmeyer, Johannes Buchner
Summary: Fusion of ACE2 with IgM-Fc produces hexameric ACE2-IgM-Fc proteins that neutralize patient-isolated SARS-CoV and SARS-CoV-2 variants effectively. These fusion proteins can be produced efficiently in mammalian cells and exhibit up to 96-fold higher potency in neutralizing the infectious virus compared to monomeric ACE2-IgM-Fc. Furthermore, the ACE2-IgM fusion shows increased neutralization efficiency for the highly infectious SARS-CoV-2 Omicron variant compared to the prototype SARS-CoV-2.
COMMUNICATIONS BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Mariam Mohamadi, David Goricanec, Gerhard Wagner, Franz Hagn
Summary: G protein-coupled receptors (GPCRs) are important drug targets and the high-resolution structures of GPCRs have provided great insights. However, understanding the dynamic nature of GPCRs is equally important and can be obtained by NMR spectroscopy. In this study, the NMR sample optimization of the neurotensin receptor type 1 (NTR1) variant HTGH4 was performed using size exclusion chromatography, thermal stability measurements, and 2D-NMR experiments. The short-chain lipid DH7PC was identified as a promising membrane mimetic for high-resolution NMR experiments. NMR and hydrogen deuterium exchange (HDX) mass spectrometry experiments were used to probe structural changes at the ligand binding site in different functional states.
JOURNAL OF STRUCTURAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Umut Guensel, Kai Kloepfer, Elisabeth Haeusler, Manuel Hitzenberger, Bettina Boelter, Laura E. Sperl, Martin Zacharias, Juergen Soll, Franz Hagn
Summary: Triose phosphates (TPs) are exported from chloroplasts into the cytosol across the inner and outer envelope membranes. The mode of action of transporters in the outer envelope remains unclear. The structure of the outer envelope protein 21 (OEP21) from garden pea was determined, revealing its cone-shaped beta-barrel structure and positively charged interior that facilitates binding and translocation of metabolites. The channel is stabilized by ATP and may provide a means of controlling metabolite transport across the outer envelope.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2023)
Article
Biology
Georg J. J. Rottenaicher, Ramona M. M. Absmeier, Laura Meier, Martin Zacharias, Johannes Buchner
Summary: Biophysical approaches reveal how a mutation in the constant light chain domain destabilizes the antibody and promotes amyloid formation in light chain (AL) amyloidosis. The mutation prevents dimerization of the light chain, weakens stability of the constant domain, and enhances proteolytic cleavage. These findings provide insights into the pathogenic mechanisms of AL amyloidosis and highlight the role of the constant domain in preventing amyloid fibril formation.
COMMUNICATIONS BIOLOGY
(2023)
Article
Biology
Hristo L. Svilenov, Florent Delhommel, Till Siebenmorgen, Florian Ruehrnoessl, Grzegorz M. Popowicz, Alwin Reiter, Michael Sattler, Carsten Brockmeyer, Johannes Buchner
Summary: The solution structure, stability, and dynamics of a broadly-acting antiviral ACE2-IgG-Fc fusion protein are determined. Small chemical compounds binding to ACE2 can be used to drastically increase the thermal stability of the ACE2 domain. Our findings reveal a general concept for stabilizing the labile receptor segments of therapeutic antiviral fusion proteins by chemical compounds.
COMMUNICATIONS BIOLOGY
(2023)