Abstract
Structures of peptide-loaded major histocompatibility complex class I (pMHC-I) and class II (pMHC-II) complexes are similar. However, whereas pMHC-II complexes include similar-sized IIα and IIβ chains, pMHC-I complexes include a heavy chain (HC) and a single domain molecule β2-microglobulin (β2-m). Recently, we elucidated several pMHC-I and pMHC-II structures of primitive vertebrate species. In the present study, a comprehensive comparison of pMHC-I and pMHC-II structures helps to understand pMHC structural evolution and supports the earlier proposed—though debated—direction of MHC evolution from class II-type to class I. Extant pMHC-II structures share major functional characteristics with a deduced MHC-II-type homodimer ancestor. Evolutionary establishment of pMHC-I presumably involved important new functions such as (i) increased peptide selectivity by binding the peptides in a closed groove (ii), structural amplification of peptide ligand sequence differences by binding in a non-relaxed fashion, and (iii) increased peptide selectivity by syngeneic heterotrimer complex formation between peptide, HC, and β2-m. These new functions were associated with structures that since their establishment in early pMHC-I have been very well conserved, including a shifted and reorganized P1 pocket (aka A pocket), and insertion of a β2-m hydrophobic knob into the peptide binding domain β-sheet floor. A comparison between divergent species indicates better sequence conservation of peptide binding domains among MHC-I than among MHC-II, agreeing with more demanding interactions within pMHC-I complexes. In lungfishes, genes encoding fusions of all MHC-IIα and MHC-IIβ extracellular domains were identified, and although these lungfish genes presumably derived from classical MHC-II, they provide an alternative mechanistic hypothesis for how evolution from class II-type to class I may have occurred.
Highlights
Major histocompatibility complex (MHC) molecules present peptide fragments of intracellularly digested protein antigens to T cells [1, 2]
To allow convenient comparisons between similar type domains of peptide-loaded major histocompatibility complex class I (pMHC-I) and pMHC-II structures, we introduced a nomenclature denoting I-a1 and II-a1 as “pa” domains (MHC peptide binding domain a), I-a2 and II-b1 as “pb” domains, b2-m and II-a2 as “ia” domains (MHC immunoglobulin superfamily (IgSF) domain a), and I-a3 and II-b2 as “ib” domains, respectively (Figures 1, 2A)
After the first pMHC-II structure was reported in 1993 by Brown et al [5], global comparisons between pMHC-I and pMHC-II structures were made [e.g., [5, 7]], but those studies did not achieve the comprehensiveness of the Saper et al [49] analysis, and the majority of the pMHC structural studies that followed focused on peptide-binding groove properties
Summary
Major histocompatibility complex (MHC) molecules present peptide fragments of intracellularly digested protein antigens to T cells [1, 2]. The ectodomain structures formed by both MHC classes consist of two membrane-distal domains which each constitute a similar half of a pseudo-symmetric unit consisting of a curved b-sheet topped by two antiparallel a-helix structures which leave a groove in between, and two membrane-proximal domains of the immunoglobulin superfamily (IgSF) C1 set. In MHC-I structures, a heavy chain (HC) comprising the two membrane-distal domains (I-a1 and I-a2), a membrane-proximal IgSF domain (I-a3), and a connecting peptide/transmembrane/cytoplasmic tail (CP/TM/CY) region, binds a free single IgSF domain molecule, b2-microglobulin (b2-m). MHC-II structures consist of two sized molecules, the IIa and IIb chains, which each possess a membrane-distal domain (II-a1 or II-b1), a membrane-proximal IgSF domain (II-a2 or II-b2), and a CP/TM/CY region. MHC-I molecules, within the groove—formed by their membrane-distal domains—which is closed at both ends, typically bind peptides of 811 amino acids (aa), most commonly of 9 aa, whereas MHC-II molecules typically bind peptides of 12-25 aa that extend beyond the ends of their open groove [7,8,9]
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