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Nature Communications Dec 2023The conformational landscapes of peptide/human leucocyte antigen (pHLA) protein complexes encompassing tumor neoantigens provide a rationale for target selection towards...
The conformational landscapes of peptide/human leucocyte antigen (pHLA) protein complexes encompassing tumor neoantigens provide a rationale for target selection towards autologous T cell, vaccine, and antibody-based therapeutic modalities. Here, using complementary biophysical and computational methods, we characterize recurrent RAS Q61 neoepitopes presented by the common HLA-A*01:01 allotype. We integrate sparse NMR restraints with Rosetta docking to determine the solution structure of NRAS/HLA-A*01:01, which enables modeling of other common RAS neoepitopes. Hydrogen/deuterium exchange mass spectrometry experiments alongside molecular dynamics simulations reveal differences in solvent accessibility and conformational plasticity across a panel of common Q61 neoepitopes that are relevant for recognition by immunoreceptors. Finally, we predict binding and provide structural models of NRAS antigens spanning the entire HLA allelic landscape, together with in vitro validation for HLA-A*01:191, HLA-B*15:01, and HLA-C*08:02. Our work provides a basis to delineate the solution surface features and immunogenicity of clinically relevant neoepitope/HLA targets for cancer therapy.
Topics: Humans; Antigens, Neoplasm; Neoplasms; Peptides; Histocompatibility Antigens; HLA-A Antigens
PubMed: 38081856
DOI: 10.1038/s41467-023-43654-9 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Aug 2021Neonatal Fc receptor (FcRn) is a specific receptor for immunoglobulin G (IgG) and albumin, which binds to them in a pH-dependent manner and prevents them from lysosomal... (Review)
Review
Neonatal Fc receptor (FcRn) is a specific receptor for immunoglobulin G (IgG) and albumin, which binds to them in a pH-dependent manner and prevents them from lysosomal degradation to keep a long plasma half-life. In addition, FcRn plays an important role in transmembrane transport of IgG and albumin and in antigen presentation. In autoimmune diseases, anti-FcRn antibody can promote the degradation of pathogenic IgG by competitive binding to FcRn. In infectious diseases, the half-life of drugs can be prolonged by increasing the affinity between therapeutic antibody and FcRn, while the combination of viral antigen and Fc fragment of IgG can cause local immune response of mucosa for disease prevention and treatment. In cancer, albumin as a carrier of anticancer drugs can achieve efficient drug delivery, and FcRn itself may be used as a predictor of the prognosis of cancer patients. This review details the functions of FcRn, highlights its role in autoimmune diseases, infectious diseases and cancer, as well as the mechanism of drug development based on FcRn, to provide a reference for the clinical application and drug development of FcRn.
Topics: Autoimmune Diseases; Histocompatibility Antigens Class I; Humans; Immunoglobulin G; Infant, Newborn; Receptors, Fc
PubMed: 34704415
DOI: 10.3724/zdxbyxb-2021-0252 -
Computers in Biology and Medicine Oct 2022Structural flexibility is an intrinsic characteristics of a protein upon interacting with other molecules, which mainly comes from the movement of a residue's side...
Structural flexibility is an intrinsic characteristics of a protein upon interacting with other molecules, which mainly comes from the movement of a residue's side chain, backbone and even an entire domain. Considering this property can be very helpful in protein binding analysis, such as epitope identification during antibody-antigen interaction. Unfortunately, to our knowledge, no approach is available at studying the dynamicity of protein binding from the computational perspective. We are pioneering a new perspective of exploring protein binding sites with considering the structural flexibility, particularly from the epitopes identification angle in antibody-antigen binding. To this end, we first obtained protein antigen structures with epitopes available, and built residue-level graphs of antigens. These graphs were highly densified subsequently by incorporating the structural flexibility. Later, the edge enriched graphs were clustered into overlapping subgraphs and were classified as epitope or non-epitope by a graph convolutional network. Experiments on epitope identification shown that the proposed flexibility-aware model markedly outperformed existing approaches by lifting the F1-score to 0.656, making a remarkable increment of 16.3% compared to the state-of-the-art. A quick study on generic protein binding site prediction also made a noteworthy improvement with increasing the F1-score by 8%. The superior performance obtained from both the specific and generic protein interaction analysis demonstrate that incorporating flexibility in computational models is helpful to strength the capability of identifying epitopes as well as general protein binding sites. This seminal study can be inspiring and promising to the wide range of protein interaction analysis.
Topics: Antigens; Binding Sites; Epitopes, B-Lymphocyte; Protein Binding
PubMed: 36084383
DOI: 10.1016/j.compbiomed.2022.106064 -
Nature Communications Jan 2023Engineered outer membrane vesicles (OMVs) derived from Gram-negative bacteria are a promising technology for the creation of non-infectious, nanoparticle vaccines...
Engineered outer membrane vesicles (OMVs) derived from Gram-negative bacteria are a promising technology for the creation of non-infectious, nanoparticle vaccines against diverse pathogens. However, antigen display on OMVs can be difficult to control and highly variable due to bottlenecks in protein expression and localization to the outer membrane of the host cell, especially for bulky and/or complex antigens. Here, we describe a universal approach for avidin-based vaccine antigen crosslinking (AvidVax) whereby biotinylated antigens are linked to the exterior of OMVs whose surfaces are remodeled with multiple copies of a synthetic antigen-binding protein (SNAP) comprised of an outer membrane scaffold protein fused to a biotin-binding protein. We show that SNAP-OMVs can be readily decorated with a molecularly diverse array of biotinylated subunit antigens, including globular and membrane proteins, glycans and glycoconjugates, haptens, lipids, and short peptides. When the resulting OMV formulations are injected in mice, strong antigen-specific antibody responses are observed that depend on the physical coupling between the antigen and SNAP-OMV delivery vehicle. Overall, these results demonstrate AvidVax as a modular platform that enables rapid and simplified assembly of antigen-studded OMVs for application as vaccines against pathogenic threats.
Topics: Animals; Mice; Bacterial Outer Membrane; Antigens; Vaccines; Membrane Proteins; Gram-Negative Bacteria; Bacterial Outer Membrane Proteins; Antigens, Bacterial; Bacterial Vaccines
PubMed: 36709333
DOI: 10.1038/s41467-023-36101-2 -
Scandinavian Journal of Immunology Feb 2021The neonatal Fc receptor (FcRn) was first recognized for its role in transfer of maternal IgG to the foetus or newborn, providing passive immunity early in life.... (Review)
Review
The neonatal Fc receptor (FcRn) was first recognized for its role in transfer of maternal IgG to the foetus or newborn, providing passive immunity early in life. However, it has become clear that the receptor is versatile, widely expressed and plays an indispensable role in both immunological and non-immunological processes throughout life. The receptor rescues immunoglobulin G (IgG) and albumin from intracellular degradation and shuttles the ligands across polarized cell barriers, in all cases via a pH-dependent binding-and-release mechanism. These processes secure distribution and high levels of both IgG and albumin throughout the body. At mucosal sites, FcRn transports IgG across polarized epithelial cells where it retrieves IgG in complex with luminal antigens that is delivered to tissue-localized immune cells. In dendritic cells (DCs), FcRn orchestrates processing of IgG-opsonized immune complexes (ICs) in concert with classical Fcγ receptors, which results in antigen presentation and cross-presentation of antigenic peptides on MHC class II and I to CD4+ and CD8+ T cells, respectively. Hence, FcRn regulates transport of the ligands within and across different types of cells, but also processing of IgG-ICs by immune cells. As such, the receptor is involved in immune surveillance and protection against infections. In this brief review, we highlight how FcRn expressed by hematopoietic and non-hematopoietic cells contributes to immune regulation at mucosal barriers-biology that can be utilized in development of biologics and subunit vaccines for non-invasive delivery.
Topics: Animals; Antigen Presentation; Antigen-Antibody Complex; Antigens; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Histocompatibility Antigens Class I; Humans; Immunoglobulin G; Immunologic Factors; Mucous Membrane; Receptors, Fc
PubMed: 33351196
DOI: 10.1111/sji.13017 -
Structure (London, England : 1993) Jan 2020Antibodies are Y-shaped proteins essential for immune response. Their capability to recognize antigens with high specificity makes them excellent therapeutic targets....
Antibodies are Y-shaped proteins essential for immune response. Their capability to recognize antigens with high specificity makes them excellent therapeutic targets. Understanding the structural basis of antibody-antigen interactions is therefore crucial for improving our ability to design efficient biological drugs. Computational approaches such as molecular docking are providing a valuable and fast alternative to experimental structural characterization for these complexes. We investigate here how information about complementarity-determining regions and binding epitopes can be used to drive the modeling process, and present a comparative study of four different docking software suites (ClusPro, LightDock, ZDOCK, and HADDOCK) providing specific options for antibody-antigen modeling. Their performance on a dataset of 16 complexes is reported. HADDOCK, which includes information to drive the docking, is shown to perform best in terms of both success rate and quality of the generated models in both the presence and absence of information about the epitope on the antigen.
Topics: Algorithms; Antigen-Antibody Complex; Computational Biology; Epitopes; Models, Molecular; Molecular Docking Simulation; Protein Conformation
PubMed: 31727476
DOI: 10.1016/j.str.2019.10.011 -
Cells Sep 2019Siglecs (Sialic acid-binding immunoglobulin-type lectins) are a I-type lectin that typically binds sialic acid. Siglecs are predominantly expressed in immune cells and... (Review)
Review
Siglecs (Sialic acid-binding immunoglobulin-type lectins) are a I-type lectin that typically binds sialic acid. Siglecs are predominantly expressed in immune cells and generate activating or inhibitory signals. They are also shown to be expressed on the surface of cells in the nervous system and have been shown to play central roles in neuroinflammation. There has been a plethora of reviews outlining the studies pertaining to Siglecs in immune cells. However, this review aims to compile the articles on the role of Siglecs in brain function and neurological disorders. In humans, the most abundant Siglecs are CD33 (Siglec-3), Siglec-4 (myelin-associated glycoprotein/MAG), and Siglec-11, Whereas in mice the most abundant are Siglec-1 (sialoadhesin), Siglec-2 (CD22), Siglec-E, Siglec-F, and Siglec-H. This review is divided into three parts. Firstly, we discuss the general biological aspects of Siglecs that are expressed in nervous tissue. Secondly, we discuss about the role of Siglecs in brain function and molecular mechanism for their function. Finally, we collate the available information on Siglecs and neurological disorders. It is intriguing to study this family of proteins in neurological disorders because they carry immunoinhibitory and immunoactivating motifs that can be vital in neuroinflammation.
Topics: Animals; Antigens, CD; Brain; Humans; Mice; Myelin-Associated Glycoprotein; N-Acetylneuraminic Acid; Nervous System Diseases; Sialic Acid Binding Ig-like Lectin 2; Sialic Acid Binding Ig-like Lectin 3; Sialic Acid Binding Immunoglobulin-like Lectins
PubMed: 31546700
DOI: 10.3390/cells8101125 -
Journal of Virology Nov 2022Rabbit hemorrhagic disease virus (RHDV) typically causes a fatal disease in rabbits. In Australia, RHDV was imported to control the feral rabbit population, while it...
Rabbit hemorrhagic disease virus (RHDV) typically causes a fatal disease in rabbits. In Australia, RHDV was imported to control the feral rabbit population, while it poses a severe threat to native rabbits in other countries. RHDV variants are genetically diverse and serological studies using antibodies isolated from infected rabbits or raised against RHDV virus-like particles (VLPs) have found RHDV variants antigenically distinct. In this study, we determined the X-ray crystal structure of an RHDV GI.2 (N11 strain) protruding (P) domain in complex with a diagnostic monoclonal antibody (2D9) Fab. We showed that 2D9 interacted with conserved and variable residues on top of the P domain with nanomolar affinity. To better illustrate 2D9 specificity, we determined the X-ray crystal structure of an RHDV GI.1b (Ast89 strain) that was a 2D9 non-binder. Structural analysis indicated that amino acid substitutions on the GI.1b P domain likely restricted 2D9 binding. Interestingly, a model of the GI.2 P domain-Fab complex superimposed onto a cryo-EM structure of an RHDV VLP revealed that 2D9 Fab molecules clashed with neighboring Fabs and indicated that there was a reduced antibody binding occupancy. Moreover, the RHDV GI.2 histo-blood group antigen (HBGA) co-factor binding site appeared obstructed when 2D9 was modeled on the VLP and suggested that 2D9 might also function by blocking HBGA attachment. Overall, this new data provides the first structural basis of RHDV antibody specificity and explains how amino acid variation at the binding site likely restricts 2D9 cross-reactivity. Isolated RHDV antibodies have been used for decades to distinguish between antigenic variants, monitor temporal capsid evolution, and examine neutralizing capacities. In this study, we provided the structural basis for an RHDV GI.2 specific diagnostic antibody (2D9) binding and reveal that a small number of amino acid substitutions at the binding site could differentiate between RHDV GI.2 and GI.1b. This novel structural information provides a framework for understanding how RHDV displays a specific antigenic epitope and engages an antibody at the atomic level. Importantly, part of the 2D9 binding region was earlier reported to contain a neutralizing epitope and our structural modeling as well as recent human norovirus antibody-mediated neutralization studies, suggest that the 2D9 antibody has the potential to block HBGA attachment. These new findings should aid in characterizing antigenic variants and advance the development of novel monoclonal antibodies for diagnostics and therapeutics.
Topics: Animals; Rabbits; Antibody Specificity; Blood Group Antigens; Caliciviridae Infections; Epitopes; Hemorrhagic Disease Virus, Rabbit
PubMed: 36326275
DOI: 10.1128/jvi.01217-22 -
Immunology and Cell Biology Mar 2022Negative selection of developing T cells plays a significant role in T-cell tolerance to self-antigen. This process relies on thymic antigen-presenting cells which...
Negative selection of developing T cells plays a significant role in T-cell tolerance to self-antigen. This process relies on thymic antigen-presenting cells which express both self-antigens and cosignaling molecules. Inducible T-cell costimulator (ICOS) belongs to the CD28 family of cosignaling molecules and binds to ICOS ligand (ICOSL). The ICOS signaling pathway plays important roles in shaping the immune response to infections, but its role in central tolerance is less well understood. Here we show that ICOSL is expressed by subsets of thymic dendritic cells and medullary thymic epithelial cells as well as thymic B cells. ICOS expression is upregulated as T cells mature in the thymus and correlates with T-cell receptor signal strength during thymic selection. We also provide evidence of a role for ICOS signaling in mediating negative selection. Our findings suggest that ICOS may fine-tune T-cell receptor signals during thymic selection contributing to the generation of a tolerant T-cell population.
Topics: Antigen-Presenting Cells; B-Lymphocytes; CD28 Antigens; Inducible T-Cell Co-Stimulator Ligand; T-Lymphocytes
PubMed: 34962663
DOI: 10.1111/imcb.12520 -
Computers in Biology and Medicine Mar 2021Due to several limitations of the only available BCG vaccine, to generate adequate protective immune responses, it is important to develop potent and cost-effective...
Due to several limitations of the only available BCG vaccine, to generate adequate protective immune responses, it is important to develop potent and cost-effective vaccines against tuberculosis (TB). In this study, we have used an immune-informatics approach to identify potential peptide based vaccine targets against TB. The proteome of Mycobacterium tuberculosis (Mtb), the causative agent of TB, was analyzed for secretory or surface localized antigenic proteins as potential vaccine candidates. The T- and B-cell epitopes as well as MHC molecule binding efficiency were identified and mapped in the modelled structures of the selected proteins. Based on antigenicity score and molecular dynamic simulation (MD) studies two peptides namely Pep-9 and Pep-15 were analyzed, modelled and docked with MHC-I and MHC-II structures. Both peptides exhibited no cytotoxicity and were able to induce proinflammatory cytokine secretion in stimulated macrophages. The molecular docking, MD and in-vitro studies of the predicted B and T-cell epitopes of Pep-9 and Pep-15 peptides with the modelled MHC structures exhibited strong binding affinity and antigenic properties, suggesting that the complex is stable, and that these peptides can be considered as a potential candidates for the development of vaccine against TB.
Topics: Epitopes, T-Lymphocyte; Histocompatibility Antigens Class II; Molecular Docking Simulation; Mycobacterium tuberculosis; Peptides
PubMed: 33450502
DOI: 10.1016/j.compbiomed.2020.104203