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Conserved Sequence Preferences Contribute to Substrate Recognition by the Proteasome.

Houqing Yu¹, Amit K Singh Gautam², Shameika R Wilmington¹

¹From the Department of Molecular Biosciences and the Department of Molecular Biosciences, Northwestern University, Evanston, Illinois 60208.

The Journal of Biological Chemistry

|May 27, 2016

Summary

Modifying protein sequences recognized by the proteasome (a cellular machine) can control protein levels. This conserved mechanism impacts cell survival and organism fitness.

Keywords:

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

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Area of Science:

Molecular Biology
Proteomics
Cell Biology

Background:

The proteasome degrades proteins, a crucial cellular process.
Proteasome substrate recognition involves specific amino acid sequences.
The N-end rule pathway is a known mechanism for protein degradation control.

Purpose of the Study:

To investigate if proteasome sequence preferences can be modulated to control protein abundance.
To determine the dynamic range of protein abundance control via sequence modification.
To assess the impact of altered proteasomal initiation on cellular fitness.

Main Methods:

Engineering of protein sequences to alter proteasomal degradation initiation sites.
Measurement of steady-state protein abundance in yeast and human cells.
Assessing yeast cell survival and fitness under varying proteasomal initiation conditions.

Main Results:

Modulating proteasomal initiation sequences tunes protein abundance over two orders of magnitude.
This level of control is comparable to the N-end rule pathway.
Altered proteasomal initiation affects yeast cell survival and fitness.
Proteasome sequence preferences are conserved across yeast and human cells.

Conclusions:

The sequence composition of protein initiation sites directly influences in vivo protein abundance.
This sequence-dependent regulation of protein stability is evolutionarily conserved.
Modulating proteasomal substrate recognition offers a novel strategy for controlling protein levels and cellular phenotype.