Abstract
Major histocompatibility complex class I (MHC-I) molecules are critical to adaptive immune defence mechanisms in vertebrate species and are encoded by highly polymorphic genes. Polymorphic sites are located close to the ligand-binding groove and entail MHC-I alleles with distinct binding specificities. Some efforts have been made to investigate the relationship between polymorphism and protein stability. However, less is known about the relationship between polymorphism and MHC-I co-evolutionary constraints. Using Direct Coupling Analysis (DCA) we found that co-evolution analysis accurately pinpoints structural contacts, although the protein family is restricted to vertebrates and comprises less than five hundred species, and that the co-evolutionary signal is mainly driven by inter-species changes, and not intra-species polymorphism. Moreover, we show that polymorphic sites in human preferentially avoid co-evolving residues, as well as residues involved in protein stability. These results suggest that sites displaying high polymorphism may have been selected during vertebrates’ evolution to avoid co-evolutionary constraints and thereby maximize their mutability.
Highlights
Major Histocompatibility Complex class I proteins (MHC-I), referred to as Human Leukocyte Antigen class I (HLA-I) in human, are expressed on the surface of cells
Our work is the first co-evolution analysis of a protein family that displays at the same time high variability between species and high polymorphism within species
As in all Direct Coupling Analysis (DCA) analyses, we focused here on sites that are distant in the sequence, which ensures that predictions of structural contacts are Polymorphic sites preferentially avoid co-evolving residues in MHC class I proteins not resulting from sequence proximity
Summary
Major Histocompatibility Complex class I proteins (MHC-I), referred to as Human Leukocyte Antigen class I (HLA-I) in human, are expressed on the surface of cells. MHC-I proteins show a very high degree of polymorphism especially around the peptide-binding groove and tens of thousands of different alleles are reported in databases like PFAM [2] or IMGT/HLA [3]. Duplication events occurred during the evolution of jawed vertebrate, which led to MHC-I polygenicity in many species [4,5]. The number of MHC-I loci differs between vertebrate species [7]. These duplication events produced 6 MHC-I genes in human all located on chromosome 6. The polygenicity and polymorphism entails the immune system of each individual with the ability to present at the cell surface a wide range of peptides from foreign pathogens
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