A relationship between the aggregation rates of α-synuclein variants and the β-sheet populations in their monomeric forms.
Intrinsically disordered proteins constitute a significant part of the human proteome and carry out a wide range of different functions, including in particular signaling and regulation. Several of these proteins are vulnerable to aggregation, and their aberrant assemblies have been associated with a variety of neurodegenerative and systemic diseases. It remains unclear, however, the extent to which the conformational properties of intrinsically disordered proteins in their monomeric states influence the aggregation behavior of these molecules. Here we report a relationship between aggregation rates and secondary structure populations in the soluble monomeric states of a series of mutational variants of α-synuclein. Overall, we found a correlation of over 90% between the changes in β-sheet populations calculated from NMR chemical shift data and the changes in aggregation rates for eight human-to-mouse chimeric mutants. These results provide support to the idea of investigating therapeutic strategies based on the stabilization of the monomeric form of intrinsically disordered proteins through the alteration of their conformational properties.
Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, United Kingdom.
Carlo
C
Camilloni
Michele
M
Vendruscolo
D000818:Animals; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics; D051846:beta-Synuclein / Q000737:chemistry* / Q000235:genetics
D011994:Recombinant Proteins; D051844:alpha-Synuclein; D051846:beta-Synuclein