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  • Perspective
  • Published:

Energy landscapes of functional proteins are inherently risky

Abstract

Evolutionary pressure for protein function leads to unavoidable sampling of conformational states that are at risk of misfolding and aggregation. The resulting tension between functional requirements and the risk of misfolding and/or aggregation in the evolution of proteins is becoming more and more apparent. One outcome of this tension is sensitivity to mutation, in which only subtle changes in sequence that may be functionally advantageous can tip the delicate balance toward protein aggregation. Similarly, increasing the concentration of aggregation-prone species by reducing the ability to control protein levels or compromising protein folding capacity engenders increased risk of aggregation and disease. In this Perspective, we describe examples that epitomize the tension between protein functional energy landscapes and aggregation risk. Each case illustrates how the energy landscapes for the at-risk proteins are sculpted to enable them to perform their functions and how the risks of aggregation are minimized under cellular conditions using a variety of compensatory mechanisms.

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Figure 1: Schematic two-dimensional functional energy landscapes.
Figure 2: CRABP1 exemplifies the structure and dynamics of the iLBP family.
Figure 3: Functional and nonfunctional serpin conformational gymnastics.
Figure 4: Folding landscape of β2m and its assembly with the MHC-1 heavy chain.
Figure 5: Competition between ubiquitin binding and aggregation for the Josephin domain of Atx3.

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Acknowledgements

We thank our many collaborators and co-authors whose experiments and ideas have contributed to our work. We also recognize that all relevant examples and references cannot be included in a short perspective such as this, and we apologize to those whose contributions we have omitted. We acknowledge, with thanks, funding from the National Institutes of Health (grants GM027616 and GM101644 to L.M.G., GM094848 to L.M.G. and A.G. and GM060418 to A.G.); the Medical Research Council (grant U117584256 to A.P.) and the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013; 322408) and the Wellcome Trust (WT092896MA to S.E.R.).

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Correspondence to Lila M Gierasch.

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Gershenson, A., Gierasch, L., Pastore, A. et al. Energy landscapes of functional proteins are inherently risky. Nat Chem Biol 10, 884–891 (2014). https://doi.org/10.1038/nchembio.1670

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