Peptide Handling by HLA-B27 Subtypes Influences Their Biological Behavior, Association with Ankylosing Spondylitis and Susceptibility to Endoplasmic Reticulum Aminopeptidase 1 (ERAP1)

Abstract

HLA-B27 is strongly associated with ankylosing spondylitis (AS). We analyzed the relationship between structure, peptide specificity, folding, and stability of the seven major HLA-B27 subtypes to determine the role of their constitutive peptidomes in the pathogenicity of this molecule. Identification of large numbers of ligands allowed us to define the differences among subtype-bound peptidomes and to elucidate the peptide features associated with AS and molecular stability. The peptides identified only in AS-associated or high thermostability subtypes with identical A and B pockets were longer and had bulkier and more diverse C-terminal residues than those found only among non-AS-associated/lower-thermostability subtypes. Peptides sequenced from all AS-associated subtypes and not from non-AS-associated ones, thus strictly correlating with disease, were very rare. Residue 116 was critical in determining peptide binding, thermodynamic properties, and folding, thus emerging as a key feature that unified HLA-B27 biology. HLA-B27 ligands were better suited to TAP transport than their N-terminal precursors, and ASassociated subtype ligands were better than those from non-AS-associated subtypes, suggesting a particular capacity of AS-associated subtypes to bind epitopes directly produced in the cytosol. Peptides identified only from ASassociated/high-thermostability subtypes showed a higher frequency of ERAP1-resistant N-terminal residues than ligands found only in non-AS-associated/low-thermostability subtypes, reflecting a more pronounced effect of ERAP1 on the former group. Our results reveal the basis for the relationship between peptide specificity and other features of HLA-B27, provide a unified view of HLA-B27 biology and pathogenicity, and suggest a larger influence of ERAP1 polymorphism on AS-associated than non-AS-associated subtypes. Molecular & Cellular

The Peptidome of Behçet's Disease–Associated HLA–B*51:01 Includes Two Subpeptidomes Differentially Shaped by Endoplasmic Reticulum Aminopeptidase 1

“…B, Comparison of the affinity for B*51:01 of the peptide subsets with Pro at position 2 (Pro2), Ala at position 2 (Ala2), or other residues (other) at position 2. The calculated affinity of the B*27:05 ligands reported by Garcia‐Medel et al for B*27:05 is included for comparison. Symbols represent individual peptides; horizontal lines the median.…”

Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) Polymorphism Relevant to Inflammatory Disease Shapes the Peptidome of the Birdshot Chorioretinopathy-Associated HLA-A*29:02 Antigen*

“…4), this implies a length-dependent optimization of affinity in the A*29:02 peptidome. In a similar analysis performed on published peptide data bases, higher theoretical affinity of 9-mers relative to longer peptides was also observed among HLA-A*02 ligands (36) but not in HLA-B*07 (36) or B*27:05 (37).…”

Structural Basis for Antigenic Peptide Recognition and Processing by Endoplasmic Reticulum (ER) Aminopeptidase 2

“…To perform this function, ERAP1 and ERAP2 have to demonstrate significant permissiveness in substrate recognition. Still, their effects on the cellular antigenic peptide repertoire as well as in vitro studies have suggested that they possess at least some sequence selectivity (23)(24)(25)(26)(27). The first crystal structures of ERAP1 and ERAP2 provided insight on this function (9,28,29).…”