Apr 5, 2020

Elucidating the signatures of proteasome-catalysed peptide splicing

BioRxiv : the Preprint Server for Biology
W. PaesPersephone Borrow

Abstract

Proteasomes catalyse 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-catalysed peptide splicing (PCPS) in the generation of non-genomically templated major histocompatibility complex class I (MHC-I)-bound cis-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-catalysed cis-splicing reactions by examination of in vitro proteasomal digests of a panel of viral- and self-derived polypeptide substrates using a tailored mass-spectrometry-based de novo sequencing 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 fac...Continue Reading

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Mentioned in this Paper

Immune Response
T-Lymphocyte
Decision Making
Genes
Conventional (Clear Cell) Renal Cell Carcinoma
Immune Response to Tumor Cell
Neoplasms
Profile (Lab Procedure)
Gene Expression
Antigen Presentation Pathway

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