Environment-transformable sequence–structure relationship: a general mechanism for proteotoxicity
- 91 Downloads
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.
KeywordsNeurodegenerative diseases Aging Proteotoxicity Membrane interaction Liquid–liquid phase separation (LLPS) Prion-like domains
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.
Compliance with ethical standards
Conflict of interest
Jianxing Song declares that he has no conflicts of interest.
This article does not contain any studies with human participants or animals performed by the author.
- Bodner RA, Outeiro TF, Altmann S, Maxwell MM, Cho SH, Hyman BT, McLean PJ, Young AB, Housman DE, Kazantsev AG (2006) Pharmacological promotion of inclusion formation: a therapeutic approach for Huntington’s and Parkinson’s diseases. Proc Natl Acad Sci U S A 103:4246–4251CrossRefPubMedPubMedCentralGoogle Scholar
- Kato M, McKnight SL (2017) Cross-β polymerization of low complexity sequence domains. Cold Spring Harb Perspect Biol 9. https://doi.org/10.1101/cshperspect.a023598
- Lim L, Lu Y, Song J (2016b) Unlocked capacity of proteins to attack membranes characteristic of aggregation: the evil for diseases and aging from Pandora’s box. bioRxiv 071274. http://dx.doi.org/10.1101/071274
- Lu Y, Lim L, Tan Y, Wang L, Song J (2016) Mechanisms of self-assembly and fibrillization of the prion-like domains. bioRxiv 065631. https://doi.org/10.1101/065631
- Lu Y, Lim L, Song J. (2017b) RRM domain of ALS/FTD-causing FUS interacts with membrane: an anchor of membraneless organelles to membranes? bioRxiv 122671. https://doi.org/10.1101/122671
- Murray DT, Kato M, Lin Y, Thurber KR, Hung I, McKnight SL, Tycko R. (2017) Structure of FUS Protein Fibrils and Its Relevance to Self-Assembly and Phase Separation of Low-Complexity Domains. Cell 171(3):615–627.e16. https://doi.org/10.1016/j.cell.2017.08.048
- Pinti DL (2005) The origin and evolution of the oceans. In Gargaud M et al. (eds) Lectures in Astrobiology. Springer, Berlin, pp 83–111. http://www.springer.com/gb/book/9783540262299
- Rayman JB, Kandel ER (2017) Functional Prions in the Brain. Cold Spring Harb Perspect Biol 9(1). https://doi.org/10.1101/cshperspect.a023671
- Shahmoradian SH et al (2017) Lewy pathology in Parkinson’s disease consists of a crowded organellar membranous medley. bioRxiv. https://doi.org/10.1101/137976
- Shukla A, Mukherjee S, Sharma S, Agrawal V, Radha Kishan KV, Guptasarma P (2004) A novel UV laser induced visible blue radiation from protein crystals and aggregates: scattering artifacts or fluorescence transitions of peptide electrons delocalized through hydrogen bonding? Arch Biochem Biophys 428:144–153CrossRefPubMedGoogle Scholar
- Song J (2013) Why do proteins aggregate? “Intrinsically insoluble proteins” and “dark mediators” revealed by studies on “insoluble proteins” solubilized in pure water. F1000 Res 2:94Google Scholar
- Zu JS, Deng HX, Lo TP, Mitsumoto H, Ahmed MS, Hung WY, Cai ZJ, Tainer JA, Siddique T (1997) Exon 5 encoded domain is not required for the toxic function of mutant SOD1 but essential for the dismutase activity: identification and characterization of two new SOD1 mutations associated with familial amyotrophic lateral sclerosis. Neurogenetics 1:65–71CrossRefPubMedGoogle Scholar