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MBE Advance Access published online on May 23, 2008
Molecular Biology and Evolution, doi:10.1093/molbev/msn122
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© The Author 2008. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Letter

Natural selection against protein aggregation on self-interacting and essential proteins in yeast, fly and worm

Yiwen Chen1,2,* and Nikolay V. Dokholyan1,3,{dagger}

1 Department of Biochemistry and Biophysics
2 Department of Physics and Astronomy
3 Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599

{dagger} Corresponding author: Dokholyan, N.V. (dokh{at}med.unc.edu).

Received for publication March 26, 2008. Revision received May 14, 2008. Accepted for publication May 19, 2008.

Protein aggregation is the phenomenon of protein self-association potentially leading to detrimental effects on physiology, which is closely-related to numerous human diseases such as Alzheimer's and Parkinson's disease. Despite progress in understanding the mechanism of protein aggregation, how natural selection against protein aggregation acts on subunits of protein complexes and on proteins with different contributions to organism fitness remains largely unknown. Here, we perform a proteome-wide analysis by using an experimentally-validated algorithm TANGO and utilizing sequence, interactomic and phenotype-based functional genomic data from yeast, fly and nematode. We find that proteins that are capable of forming homo-oligomeric complex have lower aggregation propensity compared with proteins that do not function as homo-oligomer. Further, proteins that are essential to the fitness of an organism have lower aggregation propensity compared with non-essential ones. Our finding suggests that the selection force against protein aggregation acts across different hierarchies of biological system.

Key Words: natural selection • protein aggregation • functional genomics • proteome

* Present address: Department of Genetics, Harvard Medical School, Boston, MA 02115


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