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Maximum entropy determination of mammalian proteome dynamics.

Accepted version
Peer-reviewed

Type

Article

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Authors

Garcia, Gonzalo A 
Collins, Galen A 

Abstract

Full understanding of proteostasis and energy utilization in cells will require knowledge of the fraction of cell proteins being degraded with different half-lives and their rates of synthesis. We therefore developed a method to determine such information that combines mathematical analysis of protein degradation kinetics obtained in pulse-chase experiments with Bayesian data fitting using the maximum entropy principle. This approach will enable rapid analyses of whole-cell protein dynamics in different cell types, physiological states, and neurodegenerative disease. Using it, we obtained surprising insights about protein stabilities in cultured cells normally and upon activation of proteolysis by mTOR inhibition and increasing cAMP or cGMP. It revealed that >90% of protein content in dividing mammalian cell lines is long-lived, with half-lives of 24 to 200 h, and therefore comprises much of the proteins in daughter cells. The well-studied short-lived proteins (half-lives < 10 h) together comprise <2% of cell protein mass, but surprisingly account for 10 to 20% of measurable newly synthesized protein mass. Evolution thus appears to have minimized intracellular proteolysis except to rapidly eliminate misfolded and regulatory proteins.

Description

Keywords

maximum entropy, protein degradation, protein half-lives, proteome, proteostasis, Entropy, Proteome, Humans, Proteolysis, Animals, Bayes Theorem, Proteostasis, Kinetics, Cyclic AMP, TOR Serine-Threonine Kinases, Cyclic GMP

Journal Title

Proc Natl Acad Sci U S A

Conference Name

Journal ISSN

0027-8424
1091-6490

Volume Title

121

Publisher

Proceedings of the National Academy of Sciences
Sponsorship
European Research Council (337969)