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Environment-transformable sequence–structure relationship: a general mechanism for proteotoxicity

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Abstract

In his Nobel Lecture, Anfinsen stated “the native conformation is determined by the totality of interatomic interactions and hence by the amino acid sequence, in a given environment.” As aqueous solutions and membrane systems co-exist in cells, proteins are classified into membrane and non-membrane proteins, but whether one can transform one into the other remains unknown. Intriguingly, many well-folded non-membrane proteins are converted into “insoluble” and toxic forms by aging- or disease-associated factors, but the underlying mechanisms remain elusive. In 2005, we discovered a previously unknown regime of proteins seemingly inconsistent with the classic “Salting-in” dogma: “insoluble” proteins including the integral membrane fragments could be solubilized in the ion-minimized water. We have thus successfully studied “insoluble” forms of ALS-causing P56S-MSP, L126Z-SOD1, nascent SOD1 and C71G-Profilin1, as well as E. coli S1 fragments. The results revealed that these “insoluble” forms are either unfolded or co-exist with their unfolded states. Most unexpectedly, these unfolded states acquire a novel capacity of interacting with membranes energetically driven by the formation of helices/loops over amphiphilic/hydrophobic regions which universally exit in proteins but are normally locked away in their folded native states. Our studies suggest that most, if not all, proteins contain segments which have the dual ability to fold into distinctive structures in aqueous and membrane environments. The abnormal membrane interaction might initiate disease and/or aging processes; and its further coupling with protein aggregation could result in radical proteotoxicity by forming inclusions composed of damaged membranous organelles and protein aggregates. Therefore, environment-transformable sequence–structure relationship may represent a general mechanism for proteotoxicity.

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Acknowledgements

I would like to thank all laboratory members, which is a long list, for their critical contributions. The studies are supported by Ministry of Education of Singapore (MOE) Tier 2 Grants MOE2015-T2-1-111 to Jianxing Song. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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  1. Department of Biological Sciences, Faculty of Science, National University of Singapore, 10 Kent Ridge Crescent, Singapore, 119260, Singapore

    Jianxing Song

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This article is part of a Special Issue on ‘Biomolecules to Bio-nanomachines - Fumio Arisaka 70th Birthday’ edited by Damien Hall, Junichi Takagi and Haruki Nakamura

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Song, J. Environment-transformable sequence–structure relationship: a general mechanism for proteotoxicity. Biophys Rev 10, 503–516 (2018). https://doi.org/10.1007/s12551-017-0369-0

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