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Thermosensitivity of growth is determined by chaperone-mediated proteome reallocation

  1. Bernhard O. Palssona,d,e,1
  1. aDepartment of Bioengineering, University of California, San Diego, La Jolla, CA 92093;
  2. bDivision of Biological Sciences, University of California, San Diego, La Jolla, CA 92093;
  3. cBioinformatics and Systems Biology, University of California, San Diego, La Jolla, CA 92093;
  4. dDepartment of Pediatrics, University of California, San Diego, La Jolla, CA 92093;
  5. eNovo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Kongens Lyngby, Denmark
  1. Edited by Eugene I. Shakhnovich, Harvard University, Cambridge, MA, and accepted by Editorial Board Member Daniel L. Hartl September 8, 2017 (received for review April 4, 2017)

Significance

How do bacteria adapt to the diverse thermal niches on earth? Evidence accumulates in the protein sequence and structural determinants of thermosensitivity and mechanisms by which molecular chaperones aid protein folding. However, a comprehensive understanding of how thermoadaptation is achieved at the systems level is still missing. Here we reconstruct an integrated genome-scale protein-folding network for Escherichia coli, termed FoldME, that couples both contributing factors to the metabolic state of a cell. FoldME simulations reproduce the asymmetrical bacterial temperature response and delineate the multiscale strategies cells use to resist unfolding stresses induced by high temperature and destabilizing mutations in a single gene. The results highlight how global proteome allocation regulates thermoadaptation through balance between chaperones for folding and translational machinery for biosynthesis.

Abstract

Maintenance of a properly folded proteome is critical for bacterial survival at notably different growth temperatures. Understanding the molecular basis of thermoadaptation has progressed in two main directions, the sequence and structural basis of protein thermostability and the mechanistic principles of protein quality control assisted by chaperones. Yet we do not fully understand how structural integrity of the entire proteome is maintained under stress and how it affects cellular fitness. To address this challenge, we reconstruct a genome-scale protein-folding network for Escherichia coli and formulate a computational model, FoldME, that provides statistical descriptions of multiscale cellular response consistent with many datasets. FoldME simulations show (i) that the chaperones act as a system when they respond to unfolding stress rather than achieving efficient folding of any single component of the proteome, (ii) how the proteome is globally balanced between chaperones for folding and the complex machinery synthesizing the proteins in response to perturbation, (iii) how this balancing determines growth rate dependence on temperature and is achieved through nonspecific regulation, and (iv) how thermal instability of the individual protein affects the overall functional state of the proteome. Overall, these results expand our view of cellular regulation, from targeted specific control mechanisms to global regulation through a web of nonspecific competing interactions that modulate the optimal reallocation of cellular resources. The methodology developed in this study enables genome-scale integration of environment-dependent protein properties and a proteome-wide study of cellular stress responses.

Footnotes

  • ?1To whom correspondence should be addressed. Email: palsson{at}ucsd.edu.
  • Author contributions: K.C. and B.O.P. designed research; K.C. and Y.G. performed research; N.M., E.J.O., and L.Y. contributed new analytic tools; K.C. analyzed data; and K.C., Y.G., and B.O.P. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission. E.I.S. is a guest editor invited by the Editorial Board.

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1705524114/-/DCSupplemental.

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