Quantitative time-resolved analysis reveals intricate, differential regulation of standard- and immuno-proteasomes
Author(s)
Type
Journal Article
Abstract
Proteasomal protein degradation is a key determinant of protein half-life and hence of cellular processes ranging from basic metabolism to a host of immunological processes. Despite its importance the mechanisms regulating proteasome activity are only incompletely understood. Here we use an iterative and tightly integrated experimental and modelling approach to develop, explore and validate mechanistic models of proteasomal peptide-hydrolysis dynamics. The 20S proteasome is a dynamic enzyme and its activity varies over time because of interactions between substrates and products and the proteolytic and regulatory sites; the locations of these sites and the interactions between them are predicted by the model, and experimentally supported. The analysis suggests that the rate-limiting step of hydrolysis is the transport of the substrates into the proteasome. The transport efficiency varies between human standard- and immuno-proteasomes thereby impinging upon total degradation rate and substrate cleavage-site usage.
Date Issued
2015-09-22
Date Acceptance
2015-09-22
Citation
eLife, 2015, 4
ISSN
2050-084X
Publisher
eLife Sciences Publications
Journal / Book Title
eLife
Volume
4
Copyright Statement
© 2015, Liepe et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
License URL
Sponsor
Wellcome Trust
The Royal Society
Human Frontier Science Program
Biotechnology and Biological Sciences Research Council (BBSRC)
NC3Rs (National Centre for the Replacement, Refinement and Reduction of Animals in Research)
Grant Number
086763/Z/08/Z
WRMA09R3/HLL
RGP0061/2011
BB/K003909/1
NC/K001949/1
Subjects
Science & Technology
Life Sciences & Biomedicine
Biology
Life Sciences & Biomedicine - Other Topics
APPROXIMATE BAYESIAN COMPUTATION
PEPTIDE HYDROLYSIS
MODEL SELECTION
20S PROTEASOME
SENSITIVITY-ANALYSIS
PROTEIN SUBSTRATE
SYSTEMS BIOLOGY
CORE PARTICLE
S PROTEASOME
IMMUNOPROTEASOME
Bayesian analysis
biophysics
computational biology
experimental design
functional analysis
human
mouse
proteasome regulation
proteasome structure
structural biology
systems biology
Publication Status
Published
Article Number
e07545