Article
Multidisciplinary Sciences
Ines Katharina Mueller, Christian Winter, Christoph Thomas, Robbert M. Spaapen, Simon Trowitzsch, Robert Tampe
Summary: This study reveals the molecular details of client recognition by the tapasin-ERp57 complex and emphasizes the importance of peptide proofreading. These findings contribute to understanding the selector function of tapasin and the mechanism by which multiple MHC I allomorphs are chaperoned during peptide loading and editing.
NATURE COMMUNICATIONS
(2022)
Article
Immunology
Patricia T. Illing, Andy van Hateren, Rachel Darley, Nathan P. Croft, Nicole A. Mifsud, Samuel King, Lyudmila Kostenko, Mandvi Bharadwaj, James McCluskey, Tim Elliott, Anthony W. Purcell
Summary: Abacavir hypersensitivity syndrome occurs in individuals with a specific gene expression, altering immune responses. Research shows that abacavir affects the assembly of HLA-B*57:01 complexes.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Multidisciplinary Sciences
Alexander Domnick, Christian Winter, Lukas Susac, Leon Hennecke, Mario Hensen, Nicole Zitzmann, Simon Trowitzsch, Christoph Thomas, Robert Tampe
Summary: In this study, the authors determine the structure of the editing module of the peptide loading complex (PLC) and reveal the communication between peptide-MHC I assembly and glycan processing. These findings are important for understanding the initiation of adaptive immune responses and the coordination of events in endoplasmic reticulum quality control.
NATURE COMMUNICATIONS
(2022)
Review
Immunology
David H. Margulies, Jiansheng Jiang, Javeed Ahmad, Lisa F. Boyd, Kannan Natarajan
Summary: Peptide loading of MHC-I molecules plays a critical role in the response of T cells to infections and tumors. Recent advances in structural methods have improved our understanding of the biophysical parameters that govern peptide selection, binding, and surface display. The current understanding of this cellular process is based on various approaches, and further studies are needed to explore its details and potential applications in immunization and therapy.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Chemistry, Physical
Honglin Xu, Kaiyuan Song, Lin-Tai Da
Summary: The study reveals the key intermediate states during the peptide loading process into TAPBPR-bound MHC-I and identifies the key structural factors responsible for the dynamics of peptide loading. The binding of TAPBPR at the MHC-I pocket-F reshapes the distant pocket-B through allosteric regulations, promoting the loading of the peptide. The partially loaded peptide weakens the stability of the TAPBPR-MHC interaction and affects the binding site through allosteric perturbations and direct contacts.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2022)
Article
Immunology
Denise S. M. Boulanger, Leon R. Douglas, Patrick J. Duriez, Yoyel Kang, Neil Dalchau, Edd James, Tim Elliott
Summary: Tapasin, a component of MHC I peptide loading complex, plays a key role in shaping the hierarchy of CD8+ T-cell responses to tumors and pathogens by editing the repertoire of peptides presented at the cell surface. The level of tapasin expression affects peptide off-rate and abundance, and each peptide has a unique tapasin bonus fingerprint. Optimal tapasin expression level varies for each peptide in the immunopeptidome, depending on its off-rate and abundance. This finding is important in understanding immune responses and immune escape.
FRONTIERS IN IMMUNOLOGY
(2022)
Review
Immunology
Esam Abualrous, Jana Sticht, Christian Freund
Summary: MHC loci are highly diverse in vertebrate genomes, with thousands of gene variants existing in the human population. Understanding the unique peptide binding profiles of MHC alleles and their interactions with regulators can lead to personalized immune modulation strategies for HLA-associated diseases.
CURRENT OPINION IN IMMUNOLOGY
(2021)
Review
Immunology
Andy van Hateren, Tim Elliott
Summary: The selection of peptides presented by MHC-I molecules plays a crucial role in immune responses. The proteins tapasin and TAPBPR coordinate the peptide selection process, ensuring that MHC-I molecules acquire high-affinity-binding peptides. New structural analyses have provided insights into the mechanisms of tapasin's role within the peptide-loading complex and TAPBPR's ability to independently perform peptide editing. These structures reveal the intricate interactions between tapasin, TAPBPR, and MHC-I, as well as the complementary roles of calreticulin and ERp57 in achieving peptide editing.
CURRENT OPINION IN IMMUNOLOGY
(2023)
Article
Biology
Jamina Brunnberg, Valentina Herbring, Esteban Guenther Castillo, Heike Krueger, Ralph Wieneke, Robert Tampe
Summary: The researchers established a protocol enabling optical control of the translocation of the transporter associated with antigen processing (TAP), providing insights into its function in peptide-loading complex and MHC I complex trafficking in living cells. The versatile approach has potential applications in studying other cellular pathways.
COMMUNICATIONS BIOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Sebastian Wingbermuehle, Lars Schaefer
Summary: This study investigates the partial dissociation of high-affinity peptide N-termini in two different MHC I alleles using molecular dynamics simulations, and finds that the crystal structures of these alleles only partially capture the dynamic conformational ensemble.
Article
Multidisciplinary Sciences
Fengwen Zhang, Trinity M. Zang, Eva M. Stevenson, Xiao Lei, Dennis C. Copertino, Talia M. Mota, Julie Boucau, Wilfredo F. Garcia-Beltran, R. Brad Jones, Paul D. Bieniasz
Summary: Viruses use various strategies to evade or counteract immune responses, including reducing cell surface MHC-I levels. A study found that the ORF7a protein of SARS-CoV-2 reduces MHC-I levels through multiple mechanisms, and different sarbecoviruses have varying abilities to induce MHC-I downregulation. The ORF7a protein of SARS-CoV-2 physically interacts with the MHC-I heavy chain, inhibiting the assembly of the MHC-I peptide loading complex and causing MHC-I retention in the endoplasmic reticulum.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Yi Sun, Georgia F. Papadaki, Christine A. Devlin, Julia N. Danon, Michael C. Young, Trenton J. Winters, George M. Burslem, Erik Procko, Nikolaos G. Sgourakis
Summary: Immunological chaperones tapasin and TAP binding protein, related (TAPBPR) play key roles in antigenic peptide optimization and quality control of nascent class I major histocompatibility complex (MHC-I) molecules. The polymorphic nature of MHC-I proteins leads to a range of allelic dependencies on chaperones for assembly and cell-surface expression, limiting chaperone-mediated peptide exchange to a restricted set of human leuko-cyte antigen (HLA) allotypes. By studying a chicken TAPBPR ortholog and its interactions with a repertoire of HLA allotypes, this study discovers that TAPBPR orthologs have broader allele specificity in recognizing empty MHC-I and facilitate peptide exchange by maintaining a reservoir of receptive molecules. Mutations in human TAPBPR resembling the chicken sequence are found to enhance HLA-A*01:01 expression and promote peptide exchange. These findings suggest the possibility of engineering polymorphic sites on MHC-I and chaperone surfaces to manipulate their interactions and enable chaperone-mediated peptide exchange on disease-relevant HLA alleles.
Review
Immunology
Reem Satti, Jack L. Morley, Louise H. Boyle
Summary: Since its discovery over two decades ago, extensive studies have investigated the function of Transporter associated with antigen processing-binding protein-related (TAPBPR) in the MHC-I antigen processing and presentation pathway. Recently, TAPBPR, a chaperone and peptide editor, was found to have structural similarities with tapasin:MHC-I structures. However, the mechanisms by which TAPBPR selectively loads high-affinity peptides on MHC-I molecules remain debated.
CURRENT OPINION IN IMMUNOLOGY
(2023)
Article
Multidisciplinary Sciences
Sunesh Sethumadhavan, Marie Barth, Robbert M. Spaapen, Carla Schmidt, Simon Trowitzsch, Robert Tampe
Summary: This study reveals that surface presentation of MHC I is differently affected by viral factors ICP47 and US6, indicating the impact of antigenic differences. The findings suggest that different inhibitory mechanisms and conformational states influence MHC I surface presentation across allotypes.
SCIENTIFIC REPORTS
(2022)
Review
Immunology
Karthik Dhatchinamoorthy, Jeff D. Colbert, Kenneth L. Rock
Summary: Loss of MHC I antigen presentation is common in many cancers, which may impair immune responses and affect the efficacy of immunotherapy. Studies have discussed underlying mechanisms through which some cancers evade immune killing by shutting down the MHC I pathway, and proposed potential strategies to overcome this limitation.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Chemistry, Multidisciplinary
M. Florencia Sanchez, Marina S. Dietz, Ulrike Mueller, Julian Weghuber, Karl Gatterdam, Ralph Wieneke, Mike Heilemann, Peter Lanzerstorfer, Robert Tampe
Summary: Membrane receptor clustering is important for cell-cell communication, but its physiological role in cell signaling is still unclear. In this study, the researchers developed a dynamic platform to induce cluster formation of neuropeptide Y2 hormone receptors (Y2R) and found that receptor clustering enhanced the cell's response to ligands and played a key role in cell signaling.
Review
Biochemistry & Molecular Biology
M. Florencia Sanchez, Robert Tampe
Summary: Cell-surface receptors play a crucial role in mediating communication between cells and their environment. The organization of receptors on the cell membrane and the formation of dynamic receptor clusters are important for signal transduction and cell signaling. Recent studies have shown that receptor clustering can modulate transmembrane signaling even in the absence of natural ligands. This review discusses the latest findings on how ligand-independent receptor clustering regulates signaling, focusing on the biological relevance and unraveling of this phenomenon using advanced technologies such as DNA nanotechnology, optogenetics, and optochemistry.
TRENDS IN BIOCHEMICAL SCIENCES
(2023)
Article
Chemistry, Multidisciplinary
Hong-Guen Lee, Avinash Dhamija, Chandan K. Das, Kyeng Min Park, Young-Tae Chang, Lars V. Schaefer, Kimoon Kim
Summary: This study presents synthetic monosaccharide channels based on shape-persistent organic cages, porphyrin boxes (PBs), for facile transmembrane transport of glucose and fructose. PBs have a higher transport rate for glucose and fructose compared to disaccharides, demonstrated by enzyme assays and molecular dynamics simulations. The transport rate can be controlled by changing the length of the alkyl chains on the cage windows. When the natural glucose transporter GLUT1 is blocked, PBs are able to transport glucose across living-cell membranes and enhance cell viability. Time-dependent live-cell imaging and MTT assays confirm the cyto-compatibility of PBs. The monosaccharide-selective transport ability of PBs resembles that of natural glucose transporters (GLUTs), which play critical roles in biological functions.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Physical
Andreas Rutz, Chandan K. Das, Andrea Fasano, Jan Jaenecke, Shanika Yadav, Ulf-Peter Apfel, Vera Engelbrecht, Vincent Fourmond, Christophe Leger, Lars Schaefer, Thomas Happe
Summary: The active site of [FeFe]-hydrogenases degrades upon contact with oxygen, but the protein structure of a certain hydrogenase (CbA5H) allows its active site to be protected, reducing degradation caused by oxygen. By modifying the surface residue, the hydrogenase's resistance to oxygen can be increased.
Article
Chemistry, Physical
Benedikt Soeldner, Kristof Grohe, Peter Neidig, Jelena Auch, Sebastian Blach, Alexander Klein, Suresh K. Vasa, Lars V. Schaefer, Rasmus Linser
Summary: Understanding macromolecular function, interactions, and stability requires detailed assessment of conformational ensembles. Limited by the qualitative or low abundance of solid-state nuclear magnetic resonance internuclear distance information, accurately elucidating the spatial dynamics of solid proteins at physiological temperatures is challenging. However, this study demonstrates unprecedented access to abundant proton-proton internuclear distances, enabling accurate molecular dynamics simulations and providing atomic-level spatial details of conformational dynamics in various biomolecular systems.
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
(2023)
Article
Biochemistry & Molecular Biology
Samoil Sekulovski, Lukas Susac, Lukas S. Stelzl, Robert Tampe, Simon Trowitzsch
Summary: The heterotetrameric human tRNA splicing endonuclease TSEN and its associated RNA kinase CLP1 are essential for intron excision from pre-tRNAs. This study presents cryo-EM reconstructions of human TSEN with intron-containing pre-tRNAs and reveals the molecular principles of pre-tRNA recognition and cleavage. Disease mutations are also rationalized, providing insights into the pathogenesis of pontocerebellar hypoplasia.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Himanshu Singh, Chandan K. Das, Benjamin C. Buchmuller, Lars Schaefer, Daniel Summerer, Rasmus Linser
Summary: Researchers have discovered that 5-methylcytosine (mC) and its TET-oxidized derivatives exist in CpG dyads of mammalian DNA and regulate cell fate, but how they function as distinct regulatory signals is not well understood. Designing readers that selectively recognize these novel 'CpG duplex marks' presents a challenge due to their unprecedented selectivity requirements. This study demonstrates the importance of precise conformational plasticity for the selectivity of a designer reader for an oxidized CpG duplex mark.
NUCLEIC ACIDS RESEARCH
(2023)
Correction
Multidisciplinary Sciences
Rong Zhu, Daniel Canena, Mateusz Sikora, Miriam Klausberger, Hannah Seferovic, Ahmad Reza Mehdipour, Lisa Hain, Elisabeth Laurent, Vanessa Monteil, Gerald Wirnsberger, Ralph Wieneke, Robert Tampe, Nikolaus F. Kienzl, Lukas Mach, Ali Mirazimi, Yoo Jin Oh, Josef M. Penninger, Gerhard Hummer, Peter Hinterdorfer
NATURE COMMUNICATIONS
(2023)
Article
Biology
Lina Sagert, Christian Winter, Ina Ruppert, Maximilian Zehetmaier, Christoph Thomas, Robert Tampe
Summary: Adaptive immune responses are triggered by antigenic peptides presented on MHC I. The stability of peptide-MHC I complexes is facilitated by tapasin and TAPBPR, and the folding status of glycoproteins in the ER is monitored by UGGT1. In this study, the function of TAPBPR during the UGGT1-catalyzed quality control and reglucosylation of MHC I was investigated using a reconstituted in-vitro system.
Article
Chemistry, Multidisciplinary
Michael Rudolph, Robert Tampe, Benesh Joseph
Summary: ATP-binding cassette (ABC) transporters are responsible for transporting various substances across biological membranes. The transition between inward-facing (IF) and outward-facing (OF) conformations of transmembrane domains (TMDs) is crucial for the transport process. This study investigated the functional role of asymmetric nucleotide-binding sites (NBSs) in ABC transporters using pulsed electron-electron double-resonance spectroscopy. The results showed that ATP hydrolysis at the consensus NBS accelerates the reverse transition, and the degenerate NBS may regulate the kinetics of this process.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Malavika G. Kalarikkal, Christoph Drechsler, Gers Tusha, Lars V. Schaefer, David Van Craen
Summary: Chirality analysis of small molecules can be efficiently performed through streamlined chromatographic methods or with the use of chiroptical probes relying on host-guest interactions. In this study, metal-based containers known as helicates are explored for their potential in recognizing anions and conducting chirality analysis. The helicates contain triazole units that exhibit rotational freedom and can form either a meso-structure or a racemic mixture, resulting in a chiroptical response upon recognition of chiral carboxylates. This receptor-based approach offers a non-invasive and waste-free solution for high-throughput screenings.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Chemistry, Multidisciplinary
Claudia Brocks, Chandan K. Das, Jifu Duan, Shanika Yadav, Ulf-Peter Apfel, Subhasri Ghosh, Eckhard Hofmann, Martin Winkler, Vera Engelbrecht, Lars V. Schaefer, Thomas Happe
Summary: This study proposes a new strategy to improve the O-2 stability of [FeFe]-hydrogenases by blocking the O-2 diffusion pathway and protecting the catalytic cofactor.
Review
Biotechnology & Applied Microbiology
Eike F. Joest, Robert Tampe
Summary: Engineered antibodies are crucial tools in research and advanced pharmacy, as they offer both target recognition and modulation. Using light-activated antibody fragments, high spatiotemporal control over spontaneous antigen interaction can be achieved. Recent developments in optogenetic and optochemical engineering concepts have provided strategies for conditional antigen binding. These novel design approaches serve as complementary tools to enhance current and upcoming antibody technologies.
TRENDS IN BIOTECHNOLOGY
(2023)
Article
Multidisciplinary Sciences
Saumyak Mukherjee, Lars V. Schaefer
Summary: This study investigates the thermodynamic contributions of water and protein molecules to the formation of FUS protein condensates through atomistic molecular dynamics simulations. The results reveal that solvation entropy and protein-protein interactions are the main driving forces for the formation of FUS condensates.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Physical
Selina Juber, Lars V. Schafer
Summary: This study investigates the dynamics of organophosphate binding and release in heteroleptic coordination cages based on palladium(II) through the application of a Markov state model. The simulations reveal that both the bound state and the binding/unbinding pathways are highly dynamic, with different types of interactions mediating the binding. These findings highlight the dynamic nature of the host-guest system and its possible implications for the use of coordination cages as catalysts.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2023)