Hacking the Code of Amyloid Formation

Abstract

Many research efforts in the last years have been directed towards understanding the factors determining protein misfolding and amyloid formation. Protein stability and amino acid composition have been identified as the two major factors in vitro. The research of our group has been focused on understanding the relationship between amino acid sequence and amyloid formation. Our approach has been the design of simple model systems that reproduce the biophysical properties of natural amyloids. An amyloid sequence pattern was extracted that can be used to detect amyloidogenic hexapeptide stretches in proteins. We have added evidence supporting that these amyloidogenic stretches can trigger amyloid formation by non-amyloidogenic proteins. Some experimental results in other amyloid proteins will be analyzed under the conclusions obtained in these studies. Our studies together with evidences from other groups suggest that amyloid formation is the result of the interplay between a decrease of protein stability, and the presence of highly amyloidogenic regions in proteins. As many of these results have been obtained in vitro, the challenge for the next years will be to demonstrate their validity in in vivo systems.

Acknowledgments

We acknowledge Dr. Manuela Lopez de la Paz for her past and current input into these investigations. We acknowledge the support of a Spanish Ministry of Education and Science fellowship (to M. Teresa Pastor) and by a European Union grant (APOPIS, Abnormal Proteins in the Pathogenesis of Neurodegenerative Disorders) (to Alexandra Esteras-Chopo and M. Teresa Pastor).

Figures and Tables

Figure 1 The amyloid sequence pattern used to detect amyloid stretches in proteins. PROSITE syntax (www.expasy.org/prosite/). ‘[ ]’residues allowed at the position; ‘{ }’ residues forbidden at the position; ‘-’ separates each pattern element. Taken from Lòpez de la Paz and Serrano, 2004 © by The National Academy of Sciences of the USA.

Figure 2 Amyloid formation by the different N-terminus α-SH3 variants. All the proteins were incubated under similar conditions (pH 2.6, c ∼ 300 µM, t = 3 months and room temperature). 2-SH was assayed only at the lowest concentration (c ∼ 100 µM) because of solubility problems. r.t.: room temperature. Adapted from Esteras-Chopo et al, 2005 © by The National Academy of Sciences of the USA.