skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Thermosensitivity of growth is determined by chaperone-mediated proteome reallocation

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 tomore » global regulation through a web of nonspecific competing interactions that modulate the optimal reallocation of cellular resources. As a result, the methodology developed in this study enables genome-scale integration of environment-dependent protein properties and a proteome-wide study of cellular stress responses.« less

Authors:
 [1];  [2];  [3];  [1];  [1];  [4]
  1. Univ. of California, San Diego, La Jolla, CA (United States). Dept. of Bioengineering
  2. Univ. of California, San Diego, La Jolla, CA (United States). Div. of Biological Sciences
  3. Univ. of California, San Diego, La Jolla, CA (United States). Dept. of Bioengineering and Bioinformatics and Systems Biology
  4. Univ. of California, San Diego, La Jolla, CA (United States). Dept. of Bioengineering and Dept. of Pediatrics; Technical Univ. of Denmark, Lyngby (Denmark). Novo Nordisk Foundation Center for Biosustainability
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center
Sponsoring Org.:
USDOE
OSTI Identifier:
1498117
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 114; Journal Issue: 43; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; thermoadaptation; proteome allocation; bacterial growth law; genome-scale model; molecular chaperones

Citation Formats

Chen, Ke, Gao, Ye, Mih, Nathan, O’Brien, Edward J., Yang, Laurence, and Palsson, Bernhard O. Thermosensitivity of growth is determined by chaperone-mediated proteome reallocation. United States: N. p., 2017. Web. doi:10.1073/pnas.1705524114.
Chen, Ke, Gao, Ye, Mih, Nathan, O’Brien, Edward J., Yang, Laurence, & Palsson, Bernhard O. Thermosensitivity of growth is determined by chaperone-mediated proteome reallocation. United States. doi:10.1073/pnas.1705524114.
Chen, Ke, Gao, Ye, Mih, Nathan, O’Brien, Edward J., Yang, Laurence, and Palsson, Bernhard O. Tue . "Thermosensitivity of growth is determined by chaperone-mediated proteome reallocation". United States. doi:10.1073/pnas.1705524114. https://www.osti.gov/servlets/purl/1498117.
@article{osti_1498117,
title = {Thermosensitivity of growth is determined by chaperone-mediated proteome reallocation},
author = {Chen, Ke and Gao, Ye and Mih, Nathan and O’Brien, Edward J. and Yang, Laurence and Palsson, Bernhard O.},
abstractNote = {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. As a result, the methodology developed in this study enables genome-scale integration of environment-dependent protein properties and a proteome-wide study of cellular stress responses.},
doi = {10.1073/pnas.1705524114},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 43,
volume = 114,
place = {United States},
year = {2017},
month = {10}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 16 works
Citation information provided by
Web of Science

Figures / Tables:

Figure 1 Figure 1: FoldME reconstruction and validation. (A) Elementary model reactions for the three folding pathways. The flux going through each reaction is denoted Vreaction_label, and the coupling constraints are explained in the text. (B) Illustration of how temperature dependence of each biophysical property is combined to compute their collective effectmore » on cell growth. CR stands for chaperone requirement calculated from agg alone; CR(T) takes into account both agg and ∆G(T). (C) FoldME predictions (circles connected with a solid line) of relative growth rates of E. coli over temperatures, compared with data obtained from the literature (16, 50, 51) (diamonds) and in-house experiments (triangles).« less

Save / Share:

Works referenced in this record:

Hyperthermophilic Enzymes: Sources, Uses, and Molecular Mechanisms for Thermostability
journal, March 2001


Evolution of Escherichia coli for Growth at High Temperatures
journal, April 2010

  • Rudolph, Birgit; Gebendorfer, Katharina M.; Buchner, Johannes
  • Journal of Biological Chemistry, Vol. 285, Issue 25
  • DOI: 10.1074/jbc.M110.103374

Molecular Chaperones and Protein Quality Control
journal, May 2006


The Hsp70 chaperone machines of Escherichia coli: a paradigm for the repartition of chaperone functions
journal, November 2007


Emergence of robust growth laws from optimal regulation of ribosome synthesis
journal, August 2014

  • Scott, Matthew; Klumpp, Stefan; Mateescu, Eduard M.
  • Molecular Systems Biology, Vol. 10, Issue 8
  • DOI: 10.15252/msb.20145379

A Consensus Method for the Prediction of ‘Aggregation-Prone’ Peptides in Globular Proteins
journal, January 2013


Modeling Hsp70-Mediated Protein Folding
journal, July 2006


Global characterization of in vivo enzyme catalytic rates and their correspondence to in vitro k cat measurements
journal, March 2016

  • Davidi, Dan; Noor, Elad; Liebermeister, Wolfram
  • Proceedings of the National Academy of Sciences, Vol. 113, Issue 12
  • DOI: 10.1073/pnas.1514240113

Kinetic Model for the Coupling between Allosteric Transitions in GroEL and Substrate Protein Folding and Aggregation
journal, April 2008


Proteome-wide Analysis of Chaperonin-Dependent Protein Folding in Escherichia coli
journal, July 2005


The power stroke of the DnaK/DnaJ/GrpE molecular chaperone system 1 1Edited by J.Karn
journal, July 1997

  • Pierpaoli, Ezra V.; Sandmeier, Erika; Baici, Antonio
  • Journal of Molecular Biology, Vol. 269, Issue 5
  • DOI: 10.1006/jmbi.1997.1072

Soluble oligomerization provides a beneficial fitness effect on destabilizing mutations
journal, March 2012

  • Bershtein, S.; Mu, W.; Shakhnovich, E. I.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 13
  • DOI: 10.1073/pnas.1118157109

Bacterial growth laws reflect the evolutionary importance of energy efficiency
journal, December 2014

  • Maitra, Arijit; Dill, Ken A.
  • Proceedings of the National Academy of Sciences, Vol. 112, Issue 2
  • DOI: 10.1073/pnas.1421138111

Evolutionary drivers of thermoadaptation in enzyme catalysis
journal, December 2016


In silico method for modelling metabolism and gene product expression at genome scale
journal, January 2012

  • Lerman, Joshua A.; Hyduke, Daniel R.; Latif, Haythem
  • Nature Communications, Vol. 3, Issue 1
  • DOI: 10.1038/ncomms1928

Comparing and Combining Predictors of Mostly Disordered Proteins
journal, February 2005

  • Oldfield, Christopher J.; Cheng, Yugong; Cortese, Marc S.
  • Biochemistry, Vol. 44, Issue 6
  • DOI: 10.1021/bi047993o

Cell-wide analysis of protein thermal unfolding reveals determinants of thermostability
journal, February 2017

  • Leuenberger, Pascal; Ganscha, Stefan; Kahraman, Abdullah
  • Science, Vol. 355, Issue 6327
  • DOI: 10.1126/science.aai7825

Hsp70 chaperones: Cellular functions and molecular mechanism
journal, March 2005


Chaperone machines for protein folding, unfolding and disaggregation
journal, September 2013

  • Saibil, Helen
  • Nature Reviews Molecular Cell Biology, Vol. 14, Issue 10
  • DOI: 10.1038/nrm3658

Thermal Adaptation of Viruses and Bacteria
journal, April 2010


Expanded microbial genome coverage and improved protein family annotation in the COG database
journal, November 2014

  • Galperin, Michael Y.; Makarova, Kira S.; Wolf, Yuri I.
  • Nucleic Acids Research, Vol. 43, Issue D1
  • DOI: 10.1093/nar/gku1223

Individual and Collective Contributions of Chaperoning and Degradation to Protein Homeostasis in E. coli
journal, April 2015


An experimental test of evolutionary trade-offs during temperature adaptation
journal, May 2007

  • Bennett, A. F.; Lenski, R. E.
  • Proceedings of the National Academy of Sciences, Vol. 104, Issue Supplement 1
  • DOI: 10.1073/pnas.0702117104

Protein folding kinetics exhibit an Arrhenius temperature dependence when corrected for the temperature dependence of protein stability
journal, September 1997

  • Scalley, M. L.; Baker, D.
  • Proceedings of the National Academy of Sciences, Vol. 94, Issue 20
  • DOI: 10.1073/pnas.94.20.10636

Molecular chaperones in protein folding and proteostasis
journal, July 2011

  • Hartl, F. Ulrich; Bracher, Andreas; Hayer-Hartl, Manajit
  • Nature, Vol. 475, Issue 7356
  • DOI: 10.1038/nature10317

Bacterial proteostasis balances energy and chaperone utilization efficiently
journal, March 2017

  • Santra, Mantu; Farrell, Daniel W.; Dill, Ken A.
  • Proceedings of the National Academy of Sciences, Vol. 114, Issue 13
  • DOI: 10.1073/pnas.1620646114

Systems biology definition of the core proteome of metabolism and expression is consistent with high-throughput data
journal, August 2015

  • Yang, Laurence; Tan, Justin; O’Brien, Edward J.
  • Proceedings of the National Academy of Sciences, Vol. 112, Issue 34
  • DOI: 10.1073/pnas.1501384112

ProDy: Protein Dynamics Inferred from Theory and Experiments
journal, April 2011


How Evolutionary Pressure Against Protein Aggregation Shaped Chaperone Specificity
journal, February 2006

  • Rousseau, Frederic; Serrano, Luis; Schymkowitz, Joost W. H.
  • Journal of Molecular Biology, Vol. 355, Issue 5
  • DOI: 10.1016/j.jmb.2005.11.035

FoldEco: A Model for Proteostasis in E. coli
journal, March 2012


Experimental Evolution of a Facultative Thermophile from a Mesophilic Ancestor
journal, October 2011

  • Blaby, Ian K.; Lyons, Benjamin J.; Wroclawska-Hughes, Ewa
  • Applied and Environmental Microbiology, Vol. 78, Issue 1
  • DOI: 10.1128/AEM.05773-11

GroEL-mediated protein folding proceeds by multiple rounds of binding and release of nonnative forms
journal, August 1994


GroEL−GroES-Mediated Protein Folding
journal, May 2006

  • Horwich, Arthur L.; Farr, George W.; Fenton, Wayne A.
  • Chemical Reviews, Vol. 106, Issue 5
  • DOI: 10.1021/cr040435v

A Statistical Model for Predicting Protein Folding Rates from Amino Acid Sequence with Structural Class Information
journal, January 2005

  • Gromiha, M. Michael
  • Journal of Chemical Information and Modeling, Vol. 45, Issue 2
  • DOI: 10.1021/ci049757q

Protein Thermodynamics Can Be Predicted Directly from Biological Growth Rates
journal, May 2014


Physical limits of cells and proteomes
journal, October 2011

  • Dill, K. A.; Ghosh, K.; Schmit, J. D.
  • Proceedings of the National Academy of Sciences, Vol. 108, Issue 44
  • DOI: 10.1073/pnas.1114477108

Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features
journal, December 1983


Systems-Level Response to Point Mutations in a Core Metabolic Enzyme Modulates Genotype-Phenotype Relationship
journal, April 2015


The Molecular Diversity of Adaptive Convergence
journal, January 2012

  • Tenaillon, O.; Rodriguez-Verdugo, A.; Gaut, R. L.
  • Science, Vol. 335, Issue 6067, p. 457-461
  • DOI: 10.1126/science.1212986

Comparing protein folding in vitro and in vivo: foldability meets the fitness challenge
journal, February 2014


The Moderately Efficient Enzyme: Evolutionary and Physicochemical Trends Shaping Enzyme Parameters
journal, May 2011

  • Bar-Even, Arren; Noor, Elad; Savir, Yonatan
  • Biochemistry, Vol. 50, Issue 21
  • DOI: 10.1021/bi2002289

Multiscale Modeling of Metabolism and Macromolecular Synthesis in E. coli and Its Application to the Evolution of Codon Usage
journal, September 2012


Trigger Factor and DnaK possess overlapping substrate pools and binding specificities: Substrate specificities of DnaK and Trigger Factor
journal, February 2003


Predicting protein folding rates from geometric contact and amino acid sequence
journal, July 2008


Growth rate of polypeptide chains as a function of the cell growth rate in a mutant of Escherichia coli 15
journal, February 1971


Genome‐scale models of metabolism and gene expression extend and refine growth phenotype prediction
journal, January 2013

  • O'Brien, Edward J.; Lerman, Joshua A.; Chang, Roger L.
  • Molecular Systems Biology, Vol. 9, Issue 1
  • DOI: 10.1038/msb.2013.52

Multi-omic data integration enables discovery of hidden biological regularities
journal, October 2016

  • Ebrahim, Ali; Brunk, Elizabeth; Tan, Justin
  • Nature Communications, Vol. 7, Issue 1
  • DOI: 10.1038/ncomms13091

DnaK Functions as a Central Hub in the E. coli Chaperone Network
journal, March 2012


Hydration and heat stability effects on protein unfolding
journal, January 1993


Systems biology of the structural proteome
journal, March 2016


Protein Quality Control Acts on Folding Intermediates to Shape the Effects of Mutations on Organismal Fitness
journal, January 2013


Structural Systems Biology Evaluation of Metabolic Thermotolerance in Escherichia coli
journal, June 2013


Evolution of Escherichia coli to 42 °C and Subsequent Genetic Engineering Reveals Adaptive Mechanisms and Novel Mutations
journal, July 2014

  • Sandberg, Troy E.; Pedersen, Margit; LaCroix, Ryan A.
  • Molecular Biology and Evolution, Vol. 31, Issue 10
  • DOI: 10.1093/molbev/msu209

Do Chaperonins Boost Protein Yields by Accelerating Folding or Preventing Aggregation?
journal, April 2008


Escherichia coli Heat Shock Protein DnaK: Production and Consequences in Terms of Monitoring Cooking
journal, June 2003


Interdependence of Cell Growth and Gene Expression: Origins and Consequences
journal, November 2010


DnaK, DnaJ and GrpE form a cellular chaperone machinery capable of repairing heat-induced protein damage.
journal, November 1993


    Works referencing / citing this record:

    Cellular responses to reactive oxygen species are predicted from molecular mechanisms
    journal, July 2019

    • Yang, Laurence; Mih, Nathan; Anand, Amitesh
    • Proceedings of the National Academy of Sciences, Vol. 116, Issue 28
    • DOI: 10.1073/pnas.1905039116

      Figures/Tables have been extracted from DOE-funded journal article accepted manuscripts.