期刊
FRONTIERS IN IMMUNOLOGY
卷 11, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2020.563800
关键词
peptide splicing; proteasome; splicing mechanism; antigen processing; peptide epitopes
类别
资金
- Medical Research Council (MRC) [MR/K012037]
- National Institutes of Health [R01 AI 118549]
- National Institutes of Health [Duke Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery] [UM1 AI 100645]
Proteasomes catalyze the degradation of endogenous proteins into oligopeptides, but can concurrently create spliced oligopeptides through ligation of previously non-contiguous peptide fragments. Recent studies have uncovered a formerly unappreciated role for proteasome-catalyzed peptide splicing (PCPS) in the generation of non-genomically templated human leukocyte antigen class I (HLA-I)-boundcis-spliced peptides that can be targeted by CD8(+)T cells in cancer and infection. However, the mechanisms defining PCPS reactions are poorly understood. Here, we experimentally define the biochemical constraints of proteasome-catalyzedcis-splicing reactions by examination ofin vitroproteasomal digests of a panel of viral- and self-derived polypeptide substrates using a tailored mass-spectrometry-basedde novosequencing workflow. We show that forward and reverse PCPS reactions display unique splicing signatures, defined by preferential fusion of distinct amino acid residues with stringent peptide length distributions, suggesting sequence- and size-dependent accessibility of splice reactants for proteasomal substrate binding pockets. Our data provide the basis for a more informed mechanistic understanding of PCPS that will facilitate future prediction of spliced peptides from protein sequences.
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