Evidence for a partially folded intermediate in alpha-synuclein fibril formation
- PMID: 11152691
- DOI: 10.1074/jbc.M010907200
Evidence for a partially folded intermediate in alpha-synuclein fibril formation
Abstract
Intracellular proteinaceous aggregates (Lewy bodies and Lewy neurites) of alpha-synuclein are hallmarks of neurodegenerative diseases such as Parkinson's disease, dementia with Lewy bodies, and multiple systemic atrophy. However, the molecular mechanisms underlying alpha-synuclein aggregation into such filamentous inclusions remain unknown. An intriguing aspect of this problem is that alpha-synuclein is a natively unfolded protein, with little or no ordered structure under physiological conditions. This raises the question of how an essentially disordered protein is transformed into highly organized fibrils. In the search for an answer to this question, we have investigated the effects of pH and temperature on the structural properties and fibrillation kinetics of human recombinant alpha-synuclein. Either a decrease in pH or an increase in temperature transformed alpha-synuclein into a partially folded conformation. The presence of this intermediate is strongly correlated with the enhanced formation of alpha-synuclein fibrils. We propose a model for the fibrillation of alpha-synuclein in which the first step is the conformational transformation of the natively unfolded protein into the aggregation-competent partially folded intermediate.
Similar articles
-
Conformational behavior and aggregation of alpha-synuclein in organic solvents: modeling the effects of membranes.Biochemistry. 2003 Mar 11;42(9):2720-30. doi: 10.1021/bi027166s. Biochemistry. 2003. PMID: 12614167
-
Effect of familial Parkinson's disease point mutations A30P and A53T on the structural properties, aggregation, and fibrillation of human alpha-synuclein.Biochemistry. 2001 Sep 25;40(38):11604-13. doi: 10.1021/bi010616g. Biochemistry. 2001. PMID: 11560511
-
Metal-triggered structural transformations, aggregation, and fibrillation of human alpha-synuclein. A possible molecular NK between Parkinson's disease and heavy metal exposure.J Biol Chem. 2001 Nov 23;276(47):44284-96. doi: 10.1074/jbc.M105343200. Epub 2001 Sep 11. J Biol Chem. 2001. PMID: 11553618
-
Amino acid determinants of alpha-synuclein aggregation: putting together pieces of the puzzle.FEBS Lett. 2002 Jul 3;522(1-3):9-13. doi: 10.1016/s0014-5793(02)02883-1. FEBS Lett. 2002. PMID: 12095610 Review.
-
Α-synuclein misfolding and Parkinson's disease.Biochim Biophys Acta. 2012 Feb;1822(2):261-85. doi: 10.1016/j.bbadis.2011.10.002. Epub 2011 Oct 12. Biochim Biophys Acta. 2012. PMID: 22024360 Review.
Cited by
-
Structure based aggregation studies reveal the presence of helix-rich intermediate during α-Synuclein aggregation.Sci Rep. 2015 Mar 18;5:9228. doi: 10.1038/srep09228. Sci Rep. 2015. PMID: 25784353 Free PMC article.
-
How epigallocatechin gallate binds and assembles oligomeric forms of human alpha-synuclein.J Biol Chem. 2021 Jan-Jun;296:100788. doi: 10.1016/j.jbc.2021.100788. Epub 2021 May 18. J Biol Chem. 2021. PMID: 34019875 Free PMC article.
-
Binding of Dopamine to Alpha-Synuclein is Mediated by Specific Conformational States.J Am Soc Mass Spectrom. 2013 Sep;24(9):1346-54. doi: 10.1007/s13361-013-0676-z. Epub 2013 Jul 2. J Am Soc Mass Spectrom. 2013. PMID: 23817832 Free PMC article.
-
Targeting the chameleon: a focused look at α-synuclein and its roles in neurodegeneration.Mol Neurobiol. 2013 Apr;47(2):446-59. doi: 10.1007/s12035-012-8334-1. Epub 2012 Sep 1. Mol Neurobiol. 2013. PMID: 22940885 Review. No abstract available.
-
pH-dependent self-assembly of polyalanine peptides.Biophys J. 2007 Jan 1;92(1):293-302. doi: 10.1529/biophysj.106.091769. Epub 2006 Oct 13. Biophys J. 2007. PMID: 17040985 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Miscellaneous
