Article
Polymer Science
Chengyuan Wang, Marcus Weck
Summary: True tertiary architectures with defined local secondary structures are rare in synthetic systems. Adaptation of well-developed synthetic building blocks and controlling their folding through diverse interactions can be a general approach toward this goal. In this study, 3D hierarchical assemblies with distinct secondary domains were successfully synthesized through intramolecular folding of block copolymers.
MACROMOLECULAR RAPID COMMUNICATIONS
(2021)
Article
Biology
Masahiro Noji, Tatsushi Samejima, Keiichi Yamaguchi, Masatomo So, Keisuke Yuzu, Eri Chatani, Yoko Akazawa-Ogawa, Yoshihisa Hagihara, Yasushi Kawata, Kensuke Ikenaka, Hideki Mochizuki, Jozsef Kardos, Daniel E. Otzen, Vittorio Bellotti, Johannes Buchner, Yuji Goto
Summary: Noji et al. test the link between protein folding and misfolding upon heating and agitation, showing that folding and amyloid formation are separated by the supersaturation barrier of a protein, breakdown of which shifts the protein to the amyloid pathway. This study is valuable for understanding protein folding versus self-assembly and amyloidogenesis.
COMMUNICATIONS BIOLOGY
(2021)
Article
Chemistry, Medicinal
Adrian D. Hobson, Jianwen Xu, Christopher C. Marvin, Michael J. McPherson, Markus Hollmann, Michael Gattner, Kristina Dzeyk, Margaret M. Fettis, Agnieszka K. Bischoff, Lu Wang, Julia Fitzgibbons, Lu Wang, Paulin Salomon, Axel Hernandez Jr, Ying Jia, Hetal Sarvaiya, Christian A. Goess, Suzanne L. Mathieu, Ling C. Santora
Summary: To enable subcutaneous dosing, biotherapeutics need to have properties that allow high-concentration formulation and long-term stability in the formulation buffer. The introduction of drug-linkers in ADCs can increase hydrophobicity and aggregation, which are detrimental to subcutaneous dosing properties. This study demonstrates how the physicochemical properties of ADCs can be controlled by the drug-linker chemistry and prodrug chemistry, resulting in significantly improved solution stability. The use of an accelerated stress test in a minimal formulation buffer is crucial for achieving this optimization.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Zhiliang Yuan, Zhi Qu, Bo Duan, Tianyi Wang, Jiajun Xu, Bin Xia
Summary: The C-terminal domain of M-pro-C can form a 3D domain-swapped dimer and amyloid fibrils under non-denaturing and 3D domain-swappable conditions, respectively. Positive correlations between domain swapping dimerization rates and amyloid fibrillation were found, but not essential, as mutants incapable of 3D domain swapping could still form fibrils. The unpacking of the protofibril core region during 3D domain swapping accelerates the amyloid fibrillation process.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2022)
Article
Chemistry, Multidisciplinary
Patrick H. Maag, Florian Feist, Vinh X. Truong, Hendrik Frisch, Peter W. Roesky, Christopher Barner-Kowollik
Summary: We introduce a class of single-chain nanoparticles (SCNPs) that can unfold completely in response to visible light (λ(max)=415 nm). The initial folding is achieved through a simple esterification reaction of the polymer backbone, introducing bimane moieties, which allow for light-driven unfolding by reversing the ester-bond formation.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Xiangfei Song, Mengting Wang, Xiaoxu Chen, Xueying Zhang, Ying Yang, Zhijun Liu, Lishan Yao
Summary: This study investigated how the cellular environment affects electrostatic interactions between protein charges using in-cell nuclear magnetic resonance spectroscopy. The results showed that the transfer free energy in cells can modulate protein electrostatic interactions, with a larger effect on the interactions in the unfolded state compared to the folded state. This work highlights the importance of direct in-cell studies for understanding protein interactions and function.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Chemistry, Physical
Ander F. Pereira, Vinicius Piccoli, Leandro Martinez
Summary: In this study, we investigated the stabilizing effect of 2,2,2-trifluoroethanol (TFE) on protein α-helix through extensive simulations. Our results demonstrate that TFE effectively interacts with the protein backbone, excluding water and protecting the helical structure. However, the experimental findings of modified direct contacts suggest that these interactions do not significantly contribute to helix stabilization. Additionally, we found that TFE exhibits stronger non-specific interactions with helical conformations compared to coil states.
JOURNAL OF MOLECULAR LIQUIDS
(2022)
Article
Nanoscience & Nanotechnology
Weiqiang Wang, Marcos Gil-Garcia, Salvador Ventura
Summary: Grafting biomolecules onto nanostructures' surfaces is a common strategy for targeting pathogenic cells with diagnostic and therapeutic applications. Multivalent nanomaterials for dual- or multitargeting are attracting significant interest due to the limitations of using monofunctionalized nanomaterials. This study presents a modular methodology for obtaining multivalent antibody-functionalized nanomaterials with multitargeting properties, showcasing potential for immunotherapy.
ACS APPLIED MATERIALS & INTERFACES
(2021)
Article
Biochemistry & Molecular Biology
Leonore Novak, Maria Petrosino, Daniele Santorelli, Roberta Chiaraluce, Valerio Consalvi, Alessandra Pasquo, Carlo Travaglini-Allocatelli
Summary: A Phi value analysis was conducted on BRD2(2) to investigate its folding pathway, revealing that the C-terminal region serves as the initial folding nucleus, with the N-terminal region consolidating its structure later in the process. This indicates a hierarchical mechanism of protein folding with non-native interactions playing a significant role.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Georg Dultz, Sanjay K. Srikakulam, Michael Konetschnik, Tetsuro Shimakami, Nadezhda T. Doncheva, Julia Dietz, Christoph Sarrazin, Ricardo M. Biondi, Stefan Zeuzem, Robert Tampe, Olga Kalinina, Christoph Welsch
Summary: The Q80K polymorphism in the NS3-4A protease of hepatitis C virus is associated with treatment failure of direct acting antiviral agents and is highly prevalent in genotype 1a infections. This polymorphism destabilizes protease protein fold and reduces peptide substrate turnover. Epistatic substitutions at residues 91 and 174 stabilize the protein fold but inversely correlate with enzymatic activity, contributing to viral fitness through mechanisms not directly related to RNA replication.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Sujay Kumar Nandi, Raju Sarkar, Akhilesh Jaiswar, Susmita Roy, Debasish Haldar
Summary: Hybrid tripeptides with specific structures can form C-H center dot center dot center dot pi stabilized hairpin structures, and different alpha-amino acids have a minor influence on this interaction.
Review
Biochemistry & Molecular Biology
Liisa Lutter, Liam D. Aubrey, Wei-Feng Xue
Summary: Predicting the highly ordered three-dimensional structures of amyloid protein fibrils from their monomeric self-assembly precursors remains a challenging aspect of the classical protein folding problem, due to the polymorphic nature of amyloid assembly. Understanding the diversity and individuality of amyloid structures, as well as the link to biology and disease phenotypes, is essential. Current research focuses on resolving the structural basis and biological consequences of polymorphic amyloid assemblies using various techniques such as cryo-EM, ssNMR, and AFM.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Biochemical Research Methods
Chad D. Hyer, Hsien-Jung L. Lin, Connor T. Haderlie, Monica Berg, John C. Price
Summary: The structure of a protein defines its function and integrity, and quantifying protein folding stability (PFS) is crucial for understanding disease mechanisms. However, the lack of a user-friendly data processing tool has hindered PFS studies. We present C-Half, a user-friendly software with a graphical interface for calculating PFS, and expect its introduction to promote the usage of PFS in research.
JOURNAL OF PROTEOME RESEARCH
(2023)
Article
Chemistry, Multidisciplinary
Marc Mora, Stephanie Board, Olivier Languin-Cattoen, Laura Masino, Guillaume Stirnemann, Sergi Garcia-Manyes
Summary: Non-native disulfide bonds are dynamic covalent bridges formed in proteins, which can be detected using mechanical force and are associated with protein function and aggregation diseases.
Article
Medicine, Research & Experimental
Hongyu Zhang, Paul A. Dalby
Summary: Combined administration of antibody therapeutics is beneficial, but the stability of the antibodies may be affected when combined into a single product.
MOLECULAR PHARMACEUTICS
(2022)
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
Biochemistry & Molecular Biology
Thomas Lohr, Kai Kohlho, Gabriella T. Heller, Carlo Camilloni, Michele Vendruscolo
Summary: The stabilization of native states of proteins is a powerful drug discovery strategy. This study reveals that a small molecule can stabilize the intrinsically disordered state of the A beta 42 peptide associated with Alzheimer's disease through a disordered binding mechanism. This mechanism involves both enthalpic gain from local interactions and entropic gain from global effects.
ACS CHEMICAL NEUROSCIENCE
(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
Microbiology
Elio Rossi, Gabriella Leccese, Valerio Baldelli, Alessia Bibi, Emanuele Scalone, Carlo Camilloni, Moira Paroni, Paolo Landini
Summary: The pyrD gene plays a crucial role in the virulence of adherent-invasive Escherichia coli (AIEC), and there are structural differences between E. coli and human DHOD, making it a promising target for therapeutic strategies against chronic inflammation in Crohn's disease (CD).
Article
Chemistry, Multidisciplinary
Federico Ballabio, Luca Broggini, Cristina Paissoni, Xiao Han, Kaliroi Peqini, Benedetta Maria Sala, Renhua Sun, Tatyana Sandalova, Alberto Barbiroli, Adnane Achour, Sara Pellegrino, Stefano Ricagno, Carlo Camilloni
Summary: The introduction of p3P substitution in pathogen-derived epitopes presented by MHC-I can increase epitope immunogenicity. Molecular dynamics simulations show that p3P modification rigidifies APLs in solution, facilitating MHC-I loading and TCR binding. Sensitivity of TCR to the conformational dynamics of pMHC is critical for modulating TCR binding and immunogenicity.
Article
Biochemistry & Molecular Biology
Elin Karlsson, Jan Schnatwinkel, Cristina Paissoni, Eva Andersson, Christian Herrmann, Carlo Camilloni, Per Jemth
Summary: Recognition motifs that mediate protein-protein interactions are often found within longer intrinsically disordered regions. This study investigates the role of the flanking disordered regions in the interaction between the transcriptional co-activators NCOA3 and CBP. The findings suggest that the flanking regions promote binding through short-lived non-specific hydrophobic contacts, providing insight into the functional regulation mechanism of intrinsically disordered protein regions.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Emanuele Scalone, Luca Broggini, Cristina Visentin, Davide Erba, Fran Bacic Toplek, Kaliroi Peqini, Sara Pellegrino, Stefano Ricagno, Cristina Paissoni, Carlo Camilloni
Summary: Understanding the mechanisms of protein aggregation is crucial for treating over 50 incurable diseases. A new hybrid structure model presented in this study effectively captures the essential structural and kinetic aspects of protein aggregation through molecular dynamics simulations. This model can help observe the formation of primary nuclei and the growth of fibrils, providing a structural basis for designing drugs targeting amyloidogenic diseases.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(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
Robert Nechanitzky, Duygu Nechanitzky, Parameswaran Ramachandran, Gordon S. Duncan, Chunxing Zheng, Christoph Gobl, Kyle T. Gill, Jillian Haight, Andrew C. Wakeham, Bryan E. Snow, Vivian Bradaschia-Correa, Milan Ganguly, Zhibin Lu, Mary E. Saunders, Richard A. Flavell, Tak W. Mak
Summary: Choline acetyltransferase (ChAT) plays a critical role in the pathogenicity of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). ChAT-deficient Th17 cells in mice resist disease progression and show reduced brain-infiltrating immune cells. ChAT expression in Th17 cells is associated with TCR signaling, Bhlhe40 transcription factor, and increased mRNA levels of Il2, Il17, Il22, and Il23r.
CELL DEATH AND DIFFERENTIATION
(2023)
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
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)
Article
Biochemistry & Molecular Biology
Sergio Pulido, Hanna Rueckert, S. Fabio Falsone, Christoph Gobl, N. Helge Meyer, Klaus Zangger
Summary: Bacterial plasmids and chromosomes contain toxin-antitoxin (TA) loci, which are related to stress response, growth regulation, and antibiotic and environmental stress tolerance. The LDR-D locus is a type I TA system in Escherichia coli K12 bacteria, encoding a toxic peptide LdrD. The study reveals that LdrD specifically interacts with ribosomes, potentially inhibiting translation and protein synthesis, rather than damaging bacterial membranes.
BIOPHYSICAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Ankita Chadda, Alexander G. Kozlov, Binh Nguyen, Timothy M. Lohman, Eric A. Galburt
Summary: In this study, it was found that the DNA damage response in Mycobacterium tuberculosis differs from well-studied model bacteria. The DNA repair helicase UvrD1 in Mtb is activated through a redox-dependent process and is closely associated with the homo-dimeric Ku protein. Additionally, Ku protein is shown to stimulate the helicase activity of UvrD1.
JOURNAL OF MOLECULAR BIOLOGY
(2024)
