Short amino acid stretches can mediate amyloid formation in globular proteins: The Src homology 3 (SH3) case

Salvador Ventura, Jesús Zurdo, Saravanakumar Narayanan, Matilde Parreño, Ramón Mangues, Bernd Reif, Fabrizio Chiti, Elisa Giannoni, Christopher M. Dobson, Francesc X. Aviles, Luis Serrano

Research output: Contribution to journalArticleResearchpeer-review

188 Citations (Scopus)

Abstract

Protein misfolding and deposition underlie an increasing number of debilitating human disorders. We have shown that model proteins unrelated to disease, such as the Src homology 3 (SH3) domain of the p58α subunit of bovine phosphatidyl-inositol-3′-kinase (PI3-SH3), can be converted in vitro into assemblies with structural and cytotoxic properties similar to those of pathological aggregates. By contrast, homologous proteins, such as α-spectrin-SH3, lack the capability of forming amyloid fibrils at a measurable rate under any of the conditions we have so far examined. However, transplanting a small sequence stretch (6 aa) from PI3-SH3 to α-spectrin-SH3, comprising residues of the diverging turn and adjacent RT loop, creates an amyloidogenic protein closely similar in its behavior to the original PI3-SH3. Analysis of specific PI3-SH3 mutants further confirms the involvement of this region in conferring amyloidogenic properties to this domain. Moreover, the inclusion in this stretch of two consensus residues favored in SH3 sequences substantially inhibits aggregation. These findings show that short specific amino acid stretches can act as mediators or facilitators in the incorporation of globular proteins into amyloid structures, and they support the suggestion that natural protein sequences have evolved in part to code for structural characteristics other than those included in the native fold, such as avoidance of aggregation.
Original languageEnglish
Pages (from-to)7258-7263
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
DOIs
Publication statusPublished - 11 May 2004

Keywords

  • Protein aggregation
  • Protein evolution
  • Protein misfolding

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