Biology subjects

Chancellor, A.

Publications and source records attributed to Chancellor, A..

3 recordsLinked to original sources

bioRxiv2025

Ligand-responsive groove remodelling in human and macaque CD1d reveals a conserved MHC-like gating mechanism

CD1d presents lipid antigens to invariant natural killer T (iNKT) cells. We determined a high-resolution crystal structure of human CD1d bound to -galactosylceramide (-GalCer) at 1.76 [A], enabling detailed investigation of ligand-sensitive conformational flexibility at Phe84, a conserved aromatic residue that caps the F' groove. Electron density at Phe84 revealed multiple side-chain conformations, suggestive of ligand-induced plasticity. Molecular dynamics simulations indicated that the canonical rotamer is energetically favoured in the absence of a stabilising groove-occupying ligand. To assess conservation of this putative gating mechanism, we solved the first CD1d structure from a non-human primate, rhesus macaque CD1d--GalCer, at 1.83 [A] resolution. In contrast to the human complex, Phe84 in macaque CD1d adopted a fixed conformation. As this aromatic residue is conserved across CD1 isoforms and CD1d-expressing species, and mirrors gating residues in MHC class I that regulate peptide accommodation, our findings support a shared evolutionary strategy for managing antigen diversity. These data provide critical insight into the mechanisms of antigen presentation by CD1 molecules. Significance StatementThis study reveals that Phe84, a conserved aromatic residue in CD1d, may act as a ligand-responsive gate modulating F' groove accessibility. This conditional plasticity could enable binding of structurally diverse lipid antigens and appears conserved across CD1 isoforms. The mechanism parallels class I MHC, where gating residues regulate peptide presentation, suggesting an evolutionarily shared strategy for accommodating antigen diversity.

immunology↗

bioRxiv2022

Nucleobase adduct-containing metabolites are MR1 ligands that stimulate self-reactive MR1T cells

MR1T lymphocytes are a recently identified population of T cells that recognize unknown self-antigens presented by the non-polymorphic MHC-I-related molecule, MR1. MR1T cells can kill tumor cells and modulate the functions of other immune cells with promising therapeutic applications. By integrating genetic, pharmacological and biochemical approaches we identified carbonyl stress and alterations of nucleobase metabolism in tumor target cells that promote recognition by MR1 T cells. We dissected these pathways and found that nucleobase adduct-containing metabolites are self-antigens stimulating MR1T cells. Several nucleobase adducts are presented by MR1 molecules and stimulate individual MR1T cells. Our data suggest that MR1T cells are surveyor of cellular metabolic alterations occurring in conditions of metabolic stress, such as cancer, and lay the groundwork for the development of novel HLA-unrestricted T cell-based therapies.

immunology↗

bioRxiv2019

Validation of new tools to identify expanded repeats: an intronic pentamer expansion in RFC1 causes CANVAS

Genomic technologies such as Next Generation Sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG)exp] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG)11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS families and identified a core ancestral haplotype, estimated to have arisen in Europe over twenty-five thousand years ago. WGS of the four RFC1 negative CANVAS families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.

genetics↗