scholarly journals Integrative proteomics reveals exceptional diversity and versatility of mammalian humoral immunity

2020 ◽  
Author(s):  
Yufei Xiang ◽  
Zhe Sang ◽  
Lirane Bitton ◽  
Jianquan Xu ◽  
Yang Liu ◽  
...  
Keyword(s):  
Immune Response ◽  
Protein Interactions ◽  
Specific Antigen ◽  
Cellular Protein ◽  
Protein Protein Interactions ◽  
Humoral Immune ◽  
High Affinity ◽  
Interaction Interface ◽  
Systematic Understanding ◽  
Antigen Antibody

SummaryThe humoral immune response is essential for the survival of mammals. However, we still lack a systematic understanding of the specific serologic antibody repertoire in response to an antigen. We developed a proteomic strategy to survey, at an unprecedented scale, the landscapes of antigen-engaged, serum-circulating repertoires of camelid heavy-chain antibodies (hcAbs). The sensitivity and robustness of this technology were validated using three antigens spanning orders of magnitude in immune response; thousands of divergent, high-affinity hcAb families were confidently identified and quantified. Using high-throughput structural modeling, cross-linking mass spectrometry, mutagenesis, and deep learning, we mapped and analyzed the epitopes of > 100,000 antigen-antibody complexes. Our results revealed a surprising diversity of high-affinity hcAbs for specific antigen binding on a variety of dominant epitopes. hcAbs perfect both shape and charge complementarity to target challenging antigens specifically; they can rapidly evolve to recognize a conserved, promiscuous cellular protein interaction interface, unraveling the convergent force that drives protein-protein interactions.

scholarly journals Structural design principles for specific ultra-high affinity interactions between colicins/pyocins and immunity proteins

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Avital Shushan ◽  
Mickey Kosloff
Keyword(s):  
Protein Interactions ◽  
Structural Elements ◽  
Protein Protein Interactions ◽  
Immunity Protein ◽  
Rational Engineering ◽  
High Affinity ◽  
Comparative Structure ◽  
Polar Interactions ◽  
Exquisite Specificity

AbstractThe interactions of the antibiotic proteins colicins/pyocins with immunity proteins is a seminal model system for studying protein–protein interactions and specificity. Yet, a precise and quantitative determination of which structural elements and residues determine their binding affinity and specificity is still lacking. Here, we used comparative structure-based energy calculations to map residues that substantially contribute to interactions across native and engineered complexes of colicins/pyocins and immunity proteins. We show that the immunity protein α1–α2 motif is a unique structurally-dissimilar element that restricts interaction specificity towards all colicins/pyocins, in both engineered and native complexes. This motif combines with a diverse and extensive array of electrostatic/polar interactions that enable the exquisite specificity that characterizes these interactions while achieving ultra-high affinity. Surprisingly, the divergence of these contributing colicin residues is reciprocal to residue conservation in immunity proteins. The structurally-dissimilar immunity protein α1–α2 motif is recognized by divergent colicins similarly, while the conserved immunity protein α3 helix interacts with diverse colicin residues. Electrostatics thus plays a key role in setting interaction specificity across all colicins and immunity proteins. Our analysis and resulting residue-level maps illuminate the molecular basis for these protein–protein interactions, with implications for drug development and rational engineering of these interfaces.

scholarly journals Coiled-coil networking shapes cell molecular machinery

2012 ◽  
Vol 23 (19) ◽  
pp. 3911-3922 ◽  
Author(s):  
Yongqiang Wang ◽  
Xinlei Zhang ◽  
Hong Zhang ◽  
Yi Lu ◽  
Haolong Huang ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Critical Role ◽  
Coiled Coil ◽  
Coiled Coils ◽  
Protein Protein Interactions ◽  
Full Spectrum ◽  
Kinetochore Assembly ◽  
Genome Wide ◽  
Molecular Machinery ◽  
Systematic Understanding

The highly abundant α-helical coiled-coil motif not only mediates crucial protein–protein interactions in the cell but is also an attractive scaffold in synthetic biology and material science and a potential target for disease intervention. Therefore a systematic understanding of the coiled-coil interactions (CCIs) at the organismal level would help unravel the full spectrum of the biological function of this interaction motif and facilitate its application in therapeutics. We report the first identified genome-wide CCI network in Saccharomyces cerevisiae, which consists of 3495 pair-wise interactions among 598 predicted coiled-coil regions. Computational analysis revealed that the CCI network is specifically and functionally organized and extensively involved in the organization of cell machinery. We further show that CCIs play a critical role in the assembly of the kinetochore, and disruption of the CCI network leads to defects in kinetochore assembly and cell division. The CCI network identified in this study is a valuable resource for systematic characterization of coiled coils in the shaping and regulation of a host of cellular machineries and provides a basis for the utilization of coiled coils as domain-based probes for network perturbation and pharmacological applications.

scholarly journals Molecular dynamics shows complex interplay and long-range effects of post-translational modifications in yeast protein interactions

2021 ◽  
Vol 17 (5) ◽  
pp. e1008988
Author(s):  
Nikolina ŠoŠtarić ◽  
Vera van Noort
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Protein Interactions ◽  
Protein Structures ◽  
Cellular Protein ◽  
Free Energy Calculations ◽  
Protein Protein Interactions ◽  
Post Translational Modifications ◽  
Protein Properties ◽  
Dynamics Simulations

Post-translational modifications (PTMs) play a vital, yet often overlooked role in the living cells through modulation of protein properties, such as localization and affinity towards their interactors, thereby enabling quick adaptation to changing environmental conditions. We have previously benchmarked a computational framework for the prediction of PTMs’ effects on the stability of protein-protein interactions, which has molecular dynamics simulations followed by free energy calculations at its core. In the present work, we apply this framework to publicly available data on Saccharomyces cerevisiae protein structures and PTM sites, identified in both normal and stress conditions. We predict proteome-wide effects of acetylations and phosphorylations on protein-protein interactions and find that acetylations more frequently have locally stabilizing roles in protein interactions, while the opposite is true for phosphorylations. However, the overall impact of PTMs on protein-protein interactions is more complex than a simple sum of local changes caused by the introduction of PTMs and adds to our understanding of PTM cross-talk. We further use the obtained data to calculate the conformational changes brought about by PTMs. Finally, conservation of the analyzed PTM residues in orthologues shows that some predictions for yeast proteins will be mirrored to other organisms, including human. This work, therefore, contributes to our overall understanding of the modulation of the cellular protein interaction networks in yeast and beyond.

In silico specificity determination of neoantigen-reactive T-lymphocytes

2021 ◽  
Vol 67 (3) ◽  
pp. 251-258
Author(s):  
A.E. Kniga ◽  
I.V. Polyakov ◽  
A.V. Nemukhin
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Molecular Docking ◽  
Protein Interactions ◽  
Structural Features ◽  
Immune Recognition ◽  
Protein Protein Interactions ◽  
Binary Classifiers

Effective personalized immunotherapies of the future will need to capture not only the peculiarities of the patient’s tumor but also of his immune response to it. In this study, using results of in vitro high-throughput specificity assays, and combining comparative models of pMHCs and TCRs using molecular docking, we have constructed all-atom models for the putative complexes of all their possible pairwise TCR-pMHC combinations. For the models obtained we have calculated a dataset of physics-based scores and have trained binary classifiers that perform better compared to their solely sequence-based counterparts. These structure-based classifiers pinpoint the most prominent energetic terms and structural features characterizing the type of protein-protein interactions that underlies the immune recognition of tumors by T cells.

Chapter 1. Identification of Cellular Protein–Protein Interactions

2020 ◽  
pp. 1-39
Author(s):  
Caroline Benz ◽  
Eszter Kassa ◽  
Elias Tjärnhage ◽  
Sara Bergström Lind ◽  
Ylva Ivarsson
Keyword(s):  
Protein Interactions ◽  
Cellular Protein ◽  
Protein Protein Interactions

scholarly journals Identifying protein–protein interactions in somatic hypermutation

2005 ◽  
Vol 201 (4) ◽  
pp. 493-496 ◽  
Author(s):  
Myron F. Goodman ◽  
Matthew D. Scharff
Keyword(s):  
Mouse Model ◽  
Protein Interactions ◽  
Somatic Hypermutation ◽  
Model Systems ◽  
Antigen Binding ◽  
Immunoglobulin Genes ◽  
Protein Protein Interactions ◽  
Cell Systems ◽  
High Affinity ◽  
Key Players

Somatic hypermutation (SHM) in immunoglobulin genes is required for high affinity antibody–antigen binding. Cultured cell systems, mouse model systems, and human genetic deficiencies have been the key players in identifying likely SHM pathways, whereas “pure” biochemical approaches have been far less prominent, but change appears imminent. Here we comment on how, when, and why biochemistry is likely to emerge from the shadows and into the spotlight to elucidate how the somatic mutation of antibody variable (V) regions is generated.

Vaccination strategies in atherosclerosis

2011 ◽  
Vol 106 (11) ◽  
pp. 796-803 ◽  
Author(s):  
Johan Kuiper ◽  
Saskia de Jager
Keyword(s):  
Immune Response ◽  
Humoral Immune Response ◽  
Specific Antigen ◽  
The Body ◽  
Lipid Lowering ◽  
Current Status ◽  
Passive Immunisation ◽  
Humoral Immune ◽  
Vaccination Strategies ◽  
Self Antigens

SummaryThe treatment of atherosclerosis is currently based on lipid lowering in combination with anti-inflammatory therapies that slow the progression of atherosclerosis. Still, we are not able to fully inhibit the formation or progression of atherosclerotic lesions. A very effective strategy in other disease pathologies is vaccination, in which the body is challenged with the culprit protein or micro-organism in order to create a highly specific humoral immune-response. Immunisation can typically be divided into active or passive immunisation. Active immunisation occurs naturally when the body is exposed to certain microbes or antigens, but also artificially in the case of vaccination. Exposure to a microbe or antigen will result in the production of (antigen specific) antibodies. Passive immunisation is defined as the transfer of humoral immunity (as a result of antibody transfer). Another mechanism to ensure immune-protection is tolerance induction. Immune tolerance occurs naturally to prevent immune responses to ‘self-antigens’, but can also be induced to non-self antigens. Acquired tolerance to foreign antigens is accompanied by suppression of cellular and/or humoral immune response to the introduced antigen. In its most effective way, vaccination can result in a lifelong protection against the targeted pathology, and therefore the development of an atherosclerosis-specific vaccination is of high importance in the future prevention of atherosclerosis. One of the difficulties in developing effective vaccination strategies for atherosclerosis is the selection of a specific antigen to target. So far vaccination strategies have been based on targeting of lipidantigens, inflammation-derived antigens, and recently cell-based vaccination strategies have been employed; but also the cardiovascular ‘side-effects’ of infection-based vaccines are worthy of our attention. This review describes the current status-quo on classical antibody associated vaccination strategies but also includes promising immunemodulation approaches that may lead to a clinical application.

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