Biology subjects

Avila, D. W.

Publications and source records attributed to Avila, D. W..

3 recordsLinked to original sources

bioRxiv2026

Simplifying principles that underlie the highly complex peptide motif of the promiscuous chicken class I molecule, BF2*21:01

In chickens and humans, classical class I molecules of the major histocompatibility complex (MHC) have a spectrum of correlated properties, including cell surface expression and peptide repertoire. Understanding the impact of these promiscuous generalists and fastidious specialists is of considerable interest. The promiscuous BF2 molecule from the chicken B21 haplotype, BF2*21:01, binds a wide range of peptides by remodelling the peptide-binding site, allowing co-variation of the anchor residues at peptide positions P2 and Pc-2, and binding of an anchor residue at Pc. Using in vitro refolding assays with peptides and peptide libraries, determining thermostability and crystal structures, and analysing a chicken B21 cell line by immunopeptidomics, we found that BF2*21:01 will accommodate many possible combinations at P2 and Pc-2, as well as several hydrophobic amino acids at Pc. However, marked preferences for particular peptide lengths, particular amino acids at the three anchor residues, and particular combinations of amino acids at P2 and Pc-2 as well as at P3 and Pc-3 together lead to high frequencies of major peptides while still allowing the possibility of presenting a wide peptide repertoire. These simplifying principles may eventually allow predictions of pathogen peptides with stable binding for this iconic promiscuous class I molecule, as well as providing the data for more sophisticated peptide prediction methods.

immunology↗

bioRxiv2023

Kinex infers causal kinases from phosphoproteomics data

MotivationPhosphoproteomics data are essential for characterising signalling pathways, identifying drug targets, and evaluating efficacy and safety profiles of drug candidates. Emerging resources, including a substrate-specificity atlas and drug-induced phosphoproteomics profiles, may transform the inference of causal kinases. However, there is currently no open-source software that leverages insights derived from these resources. ResultsWe introduce Kinex, a workflow implemented in the same-name Python package, which infers causal serine/threonine kinases from phosphoproteomics data. Kinex allows users to score kinase-substrate interactions, perform enrichment analysis, visualise candidates of causal regulators, and query similar profiles in a database of drug-induced kinase activities. Analysing seven published studies and one newly generated dataset, we demonstrate that analysis with Kinex recovers causal effects of perturbations and reveals novel biological insights. We foresee that Kinex will become an indispensable tool for basic and translational research including drug discovery. AvailabilityKinex is released with the GNU General Public License and available at https://github.com/bedapub/kinex.

bioinformatics↗

bioRxiv2022

Minor differences in peptide presentation between chicken MHC class I molecules can explain differences in disease susceptibility

The highly polymorphic classical major histocompatibility complexes (MHCs) can confer resistance or susceptibility to diseases. The chicken MHC is known to confer decisive resistance or susceptibility to various economically-important pathogens, including the iconic oncogenic herpesvirus that causes Mareks disease (MD). Only one classical class I gene, BF2, is expressed at a high level in chickens, so it was relatively easy to discern a hierarchy from well-expressed thermostable fastidious specialist alleles to promiscuous generalist alleles that are less stable and expressed less on the cell surface. The BF2*1901 is more highly expressed and more thermostable than the closely-related BF2*1501, but the data for peptide repertoire available did not obviously correlate as expected. Here, we confirm for newly-developed chicken lines that the chicken haplotype B15 confers resistance to MD compared to B19. Using gas phase sequencing of peptide pools, and using immunopeptidomics involving mass spectroscopy, we find that the BF2*1901 binds a greater variety of amino acids in some anchor positions than BF2*1501. However, by X-ray crystallography, we find that the peptide-binding groove of BF2*1901 is narrower and shallower. Though the self-peptides bound to BF2*1901 may appear more various than those of BF2*1501, the structures show that the wider and deeper peptide-binding groove of BF2*1501 allows it to tightly accept many more peptides overall, correlating with the expected hierarchies for expression level, thermostability and MD resistance. Moreover, the 2 helix of BF2*1901 is higher than BF2*1501, potentially reducing the number of T cell clones that can recognize this fastidious class I molecule. IMPORTANCEDisease susceptibility mechanism is complicated, but chicken infection of Mareks disease (MD) is one of ideal models, considering the only one highly expressed classical MHC class I, BF2. The different susceptibility of the two close alleles BF2*1901 and BF2*1501 with minor difference of expression and thermostability is still unfathomed. Here, we confirm B15 chicken confers resistance to MD compared to B19. But the BF2*1901 binds a broader variety of anchoring peptides than BF2*1501. This mystery was solved by the structural determination of the two molecules with one similar peptide. The wider and deeper peptide-binding groove of BF2*1501 allows it to tightly accept many more peptides overall, which is concordant to the expected hierarchies for expression level, thermostability and MD resistance.

immunology↗