Short amino acid stretches can mediate amyloid formation in globular proteins: the Src homology 3 (SH3) case.
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 p58alpha 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 alpha-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 alpha-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.
Ventura
Salvador
S
Institut de Biotecnologia i de Biomedicina and Departament de Bioquimica i Biologia Molecular, Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain. salvador.ventura@uab.es
Zurdo
Jesús
J
Narayanan
Saravanakumar
S
Parreño
Matilde
M
Mangues
Ramón
R
Reif
Bernd
B
Chiti
Fabrizio
F
Giannoni
Elisa
E
Dobson
Christopher M
CM
Aviles
Francesc X
FX
Serrano
Luis
L
D000595:Amino Acid Sequence; D000682:Amyloid / Q000096:biosynthesis*; D000818:Animals; D002417:Cattle; D002942:Circular Dichroism; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry*; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013049:Spectrin / Q000737:chemistry; D018909:src Homology Domains
D000682:Amyloid; D013049:Spectrin; D019869:Phosphatidylinositol 3-Kinases