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Rationalization of the effects of mutations on peptide andprotein aggregation rates

Nature volume 424, pages 805–808 (2003)Cite this article

Abstract

In order for any biological system to function effectively, it is essential to avoid the inherent tendency of proteins to aggregate and form potentially harmful deposits1,2,3,4. In each of the various pathological conditions associated with protein deposition, such as Alzheimer's and Parkinson's diseases, a specific peptide or protein that is normally soluble is deposited as insoluble aggregates generally referred to as amyloid2,3. It is clear that the aggregation process is generally initiated from partially or completely unfolded forms of the peptides and proteins associated with each disease. Here we show that the intrinsic effects of specific mutations on the rates of aggregation of unfolded polypeptide chains can be correlated to a remarkable extent with changes in simple physicochemical properties such as hydrophobicity, secondary structure propensity and charge. This approach allows the pathogenic effects of mutations associated with known familial forms of protein deposition diseases to be rationalized, and more generally enables prediction of the effects of mutations on the aggregation propensity of any polypeptide chain.

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Figure 1: Dependence of the aggregation rate on different physicochemical parameters.
Figure 2: Calculated versus observed changes in aggregation rate upon mutation.

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Acknowledgements

We thank M. Calamai, J. Zurdo and M. Vendruscolo for critical reading of the manuscript. The Dipartimento di Scienze Biochimiche in Florence is supported by the Italian MIUR (Progetto “Genetica Molecolare” and Progetto FIRB “Folding di proteine: l'altra metà del codice genetico”). We are grateful for support from the Wellcome Trust (F.C. and C.M.D.).

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Author notes

  1. Fabrizio Chiti

    Present address: Dipartimento di Scienze Biochimiche, Università degli Studi di Firenze, Viale Morgagni 50, 50134, Firenze, Italy

Authors and Affiliations

  1. Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, UK

    Fabrizio Chiti & Christopher M. Dobson

  2. Dipartimento di Scienze Biochimiche, Università degli Studi di Firenze, Viale Morgagni 50, 50134, Firenze, Italy

    Massimo Stefani, Niccolò Taddei & Giampietro Ramponi

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  5. Christopher M. Dobson
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Corresponding author

Correspondence to Christopher M. Dobson.

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Supplementary information

41586_2003_BFnature01891_MOESM1_ESM.doc

Supplementary Information 1: In this table we report the scales of hydrophobicity, β-sheet propensity and charge for the 20 natural amino acids. These values are necessary for calculating the terms of δHydr, (δδGcoil-β + δδGα-coil) and δCharge to be used in equation 1. Further details are given in the caption to Table 1. (DOC 24 kb)

41586_2003_BFnature01891_MOESM2_ESM.doc

Supplementary Information 2: In this section we describe how the experimental data from the literature were used to determine the experimental values of ln (vmut/vwt) for each of the mutations reported in Table 1. The reader should also refer to the Methods section. (DOC 32 kb)

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Chiti, F., Stefani, M., Taddei, N. et al. Rationalization of the effects of mutations on peptide andprotein aggregation rates. Nature 424, 805–808 (2003). https://doi.org/10.1038/nature01891

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