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J Biol Chem. 2016 Jul 8;291(28):14526-39. doi: 10.1074/jbc.M116.727578. Epub 2016 May 17.

Conserved Sequence Preferences Contribute to Substrate Recognition by the Proteasome.

Author information

1
From the Department of Molecular Biosciences and the Department of Molecular Biosciences, Northwestern University, Evanston, Illinois 60208.
2
From the Department of Molecular Biosciences and.
3
the Center for Computational Biology and Bioinformatics, The University of Texas at Austin, Austin, Texas 78712.
4
the Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom, and.
5
Frontier Research Core for Life Sciences, University of Toyama, 3190 Gofuku, Toyama-shi, Toyama 930-8555, Japan.
6
From the Department of Molecular Biosciences and the Department of Molecular Biosciences, Northwestern University, Evanston, Illinois 60208, matouschek@austin.utexas.edu.

Abstract

The proteasome has pronounced preferences for the amino acid sequence of its substrates at the site where it initiates degradation. Here, we report that modulating these sequences can tune the steady-state abundance of proteins over 2 orders of magnitude in cells. This is the same dynamic range as seen for inducing ubiquitination through a classic N-end rule degron. The stability and abundance of His3 constructs dictated by the initiation site affect survival of yeast cells and show that variation in proteasomal initiation can affect fitness. The proteasome's sequence preferences are linked directly to the affinity of the initiation sites to their receptor on the proteasome and are conserved between Saccharomyces cerevisiae, Schizosaccharomyces pombe, and human cells. These findings establish that the sequence composition of unstructured initiation sites influences protein abundance in vivo in an evolutionarily conserved manner and can affect phenotype and fitness.

KEYWORDS:

ATP-dependent protease; cellular protein abundance; intrinsically disordered protein; proteasome; protein degradation; protein stability; protein targeting; protein turnover; ubiquitylation (ubiquitination)

PMID:
27226608
PMCID:
PMC4938175
DOI:
10.1074/jbc.M116.727578
[Indexed for MEDLINE]
Free PMC Article

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