Repair or Degrade: the Thermodynamic Dilemma of Cellular Protein Quality-Control

Frontiers in Molecular Biosciences

Mathieu E. Rebeaud¹  Satyam Tiwari¹  Pierre Goloubinoff¹  Paolo De Los Rios²  Bruno Fauvet³ 

[1] Department of Plant Molecular Biology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland;Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne—EPFL, Lausanne, Switzerland;Institute of Physics, School of Basic Sciences, École Polytechnique Fédérale de Lausanne—EPFL, Lausanne, Switzerland;

关键词: proteostasis;    thermodynamics;    protein repair;    chaperones;    protein degradation;   

DOI  :  10.3389/fmolb.2021.768888

来源: DOAJ

【 摘 要 】

Life is a non-equilibrium phenomenon. Owing to their high free energy content, the macromolecules of life tend to spontaneously react with ambient oxygen and water and turn into more stable inorganic molecules. A similar thermodynamic picture applies to the complex shapes of proteins: While a polypeptide is emerging unfolded from the ribosome, it may spontaneously acquire secondary structures and collapse into its functional native conformation. The spontaneity of this process is evidence that the free energy of the unstructured state is higher than that of the structured native state. Yet, under stress or because of mutations, complex polypeptides may fail to reach their native conformation and form instead thermodynamically stable aggregates devoid of biological activity. Cells have evolved molecular chaperones to actively counteract the misfolding of stress-labile proteins dictated by equilibrium thermodynamics. HSP60, HSP70 and HSP100 can inject energy from ATP hydrolysis into the forceful unfolding of stable misfolded structures in proteins and convert them into unstable intermediates that can collapse into the native state, even under conditions inauspicious for that state. Aggregates and misfolded proteins may also be forcefully unfolded and degraded by chaperone-gated endo-cellular proteases, and in eukaryotes also by chaperone-mediated autophagy, paving the way for their replacement by new, unaltered functional proteins. The greater energy cost of degrading and replacing a polypeptide, with respect to the cost of its chaperone-mediated repair represents a thermodynamic dilemma: some easily repairable proteins are better to be processed by chaperones, while it can be wasteful to uselessly try recover overly compromised molecules, which should instead be degraded and replaced. Evolution has solved this conundrum by creating a host of unfolding chaperones and degradation machines and by tuning their cellular amounts and activity rates.

【 授权许可】

Unknown