Bioinformatic analysis of functional differences between the immunoproteasome and the constitutive proteasome.
Intracellular proteins are degraded largely by proteasomes. In cells stimulated with gamma interferon, the active proteasome subunits are replaced by "immuno" subunits that form immunoproteasomes. Phylogenetic analysis of the immunosubunits has revealed that they evolve faster than their constitutive counterparts. This suggests that the immunoproteasome has evolved a function that differs from that of the constitutive proteasome. Accumulating experimental degradation data demonstrate, indeed, that the specificity of the immunoproteasome and the constitutive proteasome differs. However, it has not yet been quantified how different the specificity of two forms of the proteasome are. The main question, which still lacks direct evidence, is whether the immunoproteasome generates more MHC ligands. Here we use bioinformatics tools to quantify these differences and show that the immunoproteasome is a more specific enzyme than the constitutive proteasome. Additionally, we predict the degradation of pathogen proteomes and find that the immunoproteasome generates peptides that are better ligands for MHC binding than peptides generated by the constitutive proteasome. Thus, our analysis provides evidence that the immunoproteasome has co-evolved with the major histocompatibility complex to optimize antigen presentation in vertebrate cells.
Kesmir
Can
C
Theoretical Biology/Bioinformatics, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands. C.Kesmir@bio.uu.nl
van Noort
Vera
V
de Boer
Rob J
RJ
Hogeweg
Paulien
P
D000818:Animals; D019295:Computational Biology; D003546:Cysteine Endopeptidases / Q000276:immunology* / Q000502:physiology*; D019143:Evolution, Molecular; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics; D009097:Multienzyme Complexes / Q000276:immunology* / Q000502:physiology*; D010802:Phylogeny; D046988:Proteasome Endopeptidase Complex; D017422:Sequence Analysis, DNA; D020539:Sequence Analysis, Protein
D009097:Multienzyme Complexes; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex