Journal
ELIFE
Volume 4, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.07545
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Funding
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/G007934/1]
- Berlin Institute of Health [CRG1-TP1]
- Einstein Stiftung Berlin [A2013-174]
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) via a David Sainsbury Fellowship [NC/K001949/1]
- Human Frontier Science Program (HFSP) [RGP0061/2011]
- Leverhulme Trust [F/07058/BP]
- Royal Society Wolfson Research Merit Award
- AICE FIRE Onlus Emilia Romagna
- BBSRC [BB/K003909/1, BB/G007934/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/G007934/1, BB/K003909/1] Funding Source: researchfish
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [NC/K001949/1] Funding Source: researchfish
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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.
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