Structural Comparison Between MHC Classes I and II; in Evolution, a Class-II-Like Molecule Probably Came First

Area of Science:

• Immunology
• Evolutionary Biology
• Structural Biology

Background:

• Major histocompatibility complex (MHC) class I (pMHC-I) and class II (pMHC-II) complexes present peptides to T cells.
• pMHC-II complexes consist of IIα and IIβ chains, while pMHC-I complexes comprise a heavy chain (HC) and β2-microglobulin (β2-m).
• Recent structural studies of primitive vertebrate pMHC-I and pMHC-II complexes provide new insights into their evolution.

Purpose of the Study:

• To conduct a comprehensive structural comparison of pMHC-I and pMHC-II complexes.
• To understand the structural evolution of MHC molecules.
• To support the hypothesis of MHC evolution from class II-type to class I.

Main Methods:

• Comparative structural analysis of pMHC-I and pMHC-II complexes from primitive vertebrates.
• Examination of conserved structural features and functional adaptations.
• Analysis of sequence conservation in peptide-binding domains across divergent species.

Main Results:

• Extant pMHC-II structures resemble a deduced MHC-II-type homodimer ancestor.
• Evolution of pMHC-I involved new functions: increased peptide selectivity via a closed groove, enhanced peptide discrimination, and heterotrimer complex formation.
• Conserved pMHC-I structures include a shifted P1 pocket and a β2-m hydrophobic knob; MHC-I peptide-binding domains show greater sequence conservation than MHC-II.
• Lungfish genes with fused MHC-IIα and MHC-IIβ domains offer an alternative evolutionary pathway hypothesis.

Conclusions:

• MHC structural evolution likely proceeded from a class II-type ancestor to class I.
• Key structural innovations in pMHC-I facilitated enhanced peptide binding and discrimination.
• Conserved structural elements and sequence conservation patterns support the proposed evolutionary trajectory.