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

• DOI: 10.1073/pnas.0308249101
• Publication Date: 2004-05-04T01:08:45Z
• Authors: Salvador Ventura; Jesús Zurdo; Saravanakumar Nar...; Matilde Parreño; Ramón Mangues; Bernd Reif; Fabrizio Chiti; Elisa Giannoni; Christopher M. Do...; Francesc X. Aviles; Luis Serrano
• Keywords: Homology

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 p58α subunit bovine phosphatidyl-inositol-3′-kinase (PI3-SH3), can be converted in vitro into assemblies with structural cytotoxic properties similar those pathological aggregates. By contrast, homologous proteins, α-spectrin-SH3, lack capability forming amyloid fibrils at a measurable rate under any conditions we so far examined. However, transplanting small sequence stretch (6 aa) from PI3-SH3 comprising residues diverging turn adjacent RT loop, creates amyloidogenic protein closely its behavior original PI3-SH3. Analysis specific mutants further confirms involvement this region conferring domain. Moreover, inclusion two consensus favored SH3 sequences substantially inhibits aggregation. These findings show short amino acid stretches act mediators or facilitators incorporation globular structures, they support suggestion natural evolved part code for characteristics other than included native fold, avoidance