Cellular proteomes have broad distributions of protein stability.

Biological cells are extremely sensitive to temperature. What is the mechanism? We compute the thermal stabilities of the whole proteomes of Escherichia coli, yeast, and Caenorhabditis elegans using an analytical model and an extensive database of stabilities of individual proteins. Our results support the hypothesis that a cell's thermal sensitivities arise from the collective instability of its proteins. This model shows a denaturation catastrophe at temperatures of 49-55°C, roughly the thermal death point of mesophiles. Cells live on the edge of a proteostasis catastrophe. According to the model, it is not that the average protein is problematic; it is the tail of the distribution. About 650 of E. coli's 4300 proteins are less than 4 kcal mol(-1) stable to denaturation. And upshifting by only 4° from 37° to 41°C is estimated to destabilize an average protein by nearly 20%. This model also treats effects of denaturants, osmolytes, and other physical stressors. In addition, it predicts the dependence of cellular growth rates on temperature. This approach may be useful for studying physical forces in biological evolution and the role of climate change on biology.

[1]  Richard I. Morimoto,et al.  Adapting Proteostasis for Disease Intervention , 2008, Science.

[2]  A. Pozzi,et al.  COX2 Activity Promotes Organic Osmolyte Accumulation and Adaptation of Renal Medullary Interstitial Cells to Hypertonic Stress* , 2003, Journal of Biological Chemistry.

[3]  Alexander Souvorov,et al.  The relationship of protein conservation and sequence length , 2002, BMC Evolutionary Biology.

[4]  T. Shinohara,et al.  Cellular osmolytes reduce lens epithelial cell death and alleviate cataract formation in galactosemic rats. , 2007, Molecular vision.

[5]  R. Weinberg,et al.  The Biology of Cancer , 2006 .

[6]  J. P. Kennett,et al.  Abrupt deep-sea warming, palaeoceanographic changes and benthic extinctions at the end of the Palaeocene , 1991, Nature.

[7]  M. Ferguson,et al.  Temperature of egg incubation determines sex in Alligator mississippiensis , 1982, Nature.

[8]  James H. Brown,et al.  Kinetic effects of temperature on rates of genetic divergence and speciation. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Stephen H. Bryant,et al.  Domain size distributions can predict domain boundaries , 2000, Bioinform..

[10]  McMeekin,et al.  Applicability of a model for non‐pathogenic Escherichia coli for predicting the growth of pathogenic Escherichia coli , 1998, Journal of applied microbiology.

[11]  J. Zhang,et al.  Protein-length distributions for the three domains of life. , 2000, Trends in genetics : TIG.

[12]  J. Lepock.  Measurement of protein stability and protein denaturation in cells using differential scanning calorimetry. , 2005, Methods.

[13]  Jinbo Xu,et al.  Template‐based and free modeling by RAPTOR++ in CASP8 , 2009, Proteins.

[14]  Naiwan Hsiao,et al.  Predicting melting temperature directly from protein sequences , 2009, Comput. Biol. Chem..

[15]  M. Gerstein.  How representative are the known structures of the proteins in a complete genome? A comprehensive structural census. , 1998, Folding & design.

[16]  G. Webb,et al.  Effects of Incubation Temperature on Crocodiles and the Evolution of Reptilian Oviparity , 1989 .

[17]  Akinori Sarai,et al.  ProTherm and ProNIT: thermodynamic databases for proteins and protein–nucleic acid interactions , 2005, Nucleic Acids Res..

[18]  D. S. Coffey,et al.  Hyperthermic biology and cancer therapies: a hypothesis for the "Lance Armstrong effect". , 2006, JAMA.

[19]  L. Ivany,et al.  Cooler winters as a possible cause of mass extinctions at the Eocene/Oligocene boundary , 2000, Nature.

[20]  H. Mori,et al.  Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection , 2006, Molecular systems biology.

[21]  Zoya Ignatova,et al.  Monitoring protein stability and aggregation in vivo by real-time fluorescent labeling. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[22]  J. Zwischenberger,et al.  Oncogenic ras results in increased cell kill due to defective thermoprotection in lung cancer cells. , 2000, The Annals of thoracic surgery.

[23]  E. O’Shea,et al.  Global analysis of protein expression in yeast , 2003, Nature.

[24]  A. Dunker,et al.  Protein disorder is positively correlated with gene expression in Escherichia coli. , 2008, Journal of proteome research.

[25]  S. Lindquist,et al.  Hsp90 as a capacitor of phenotypic variation , 2002, Nature.

[26]  J. R. Brett.  Energetic Responses of Salmon to Temperature. A Study of Some Thermal Relations in the Physiology and Freshwater Ecology of Sockeye Salmon (Oncorhynchus nerkd) , 1971 .

[27]  C. Chothia,et al.  Structural assignments to the Mycoplasma genitalium proteins show extensive gene duplications and domain rearrangements. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Eugene I. Shakhnovich,et al.  Protein stability imposes limits on organism complexity and speed of molecular evolution , 2007, Proceedings of the National Academy of Sciences.

[29]  S. Ghaemmaghami,et al.  Quantitative protein stability measurement in vivo , 2001, Nature Structural Biology.

[30]  Kingshuk Ghosh,et al.  Computing protein stabilities from their chain lengths , 2009, Proceedings of the National Academy of Sciences.

[31]  M. E. Clark,et al.  Living with water stress: evolution of osmolyte systems. , 1982, Science.

[32]  Huan-Xiang Zhou,et al.  Nonadditive effects of mixed crowding on protein stability , 2009, Proteins.

[33]  C. Dobson.  Protein folding and misfolding , 2003, Nature.

[34]  Anders Blomberg,et al.  Evolutionary constraints on yeast protein size , 2006, BMC Evolutionary Biology.

[35]  S. Lindquist,et al.  Hsp90 as a capacitor for morphological evolution , 1998, Nature.

[36]  B K Shoichet,et al.  A relationship between protein stability and protein function. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[37]  A. N. Stokes,et al.  Model for bacterial culture growth rate throughout the entire biokinetic temperature range , 1983, Journal of bacteriology.

[38]  Andrew D. Robertson,et al.  Protein Structure and the Energetics of Protein Stability. , 1997, Chemical reviews.

[39]  W. Dewey,et al.  Variation in sensitivity to heat shock during the cell-cycle of Chinese hamster cells in vitro. , 1971, International journal of radiation biology and related studies in physics, chemistry, and medicine.

[40]  Tom Ross,et al.  Unifying temperature effects on the growth rate of bacteria and the stability of globular proteins. , 2005, Journal of theoretical biology.

[41]  C. Chothia,et al.  Structure, function and evolution of multidomain proteins. , 2004, Current opinion in structural biology.

[42]  S. Lowen.  The Biophysical Journal , 1960, Nature.

[43]  Eugene I Shakhnovich,et al.  Thermal adaptation of viruses and bacteria. , 2010, Biophysical journal.