title: Contribution of disulfide bonds to stability, folding, and amyloid fibril formation: the PI3-SH3 domain case.
abstract: OBJECTIVE
  The failure of proteins to fold or to remain folded very often leads to their deposition into amyloid fibrils and is the origin of a variety of human diseases. Accordingly, mutations that destabilize the native conformation are associated with pathological phenotypes in several protein models. Protein backbone cyclization by disulfide bond crosslinking strongly reduces the entropy of the unfolded state and, usually, increases protein stability. The effect of protein cyclization on the thermodynamic and kinetics of folding has been extensively studied, but little is know on its effect on aggregation reactions.
  
  
  RESULTS
  The SRC homology 3 domain (SH3) of p85α subunit of bovine phosphatidyl-inositol-3'-kinase (PI3-SH3) domain is a small globular protein, whose folding and amyloid properties are well characterized. Here we describe the effect of polypeptide backbone cyclization on both processes.
  
  
  METHODS
  We show that a cyclized PI3-SH3 variant is more stable, folds faster, aggregates slower, and forms conformationally and functionally different amyloid fibrils than the wild-type domain.
  
  
  CONCLUSIONS
  Disulfide bridges may act as key molecular determinants of both productive protein folding and deleterious aggregation reactions.
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Graña-Montes
authors.forename: Natalia S
authors.initials: NS
authors.lastname: de Groot
authors.forename: Virginia
authors.initials: V
authors.lastname: Castillo
authors.forename: Javier
authors.initials: J
authors.lastname: Sancho
authors.forename: Adrian
authors.initials: A
authors.lastname: Velazquez-Campoy
authors.forename: Salvador
authors.initials: S
authors.lastname: Ventura
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D002417:Cattle; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010084:Oxidation-Reduction; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D055550:Protein Stability; D013816:Thermodynamics; D018909:src Homology Domains
chemical_list: D000682:Amyloid; D058543:Class Ia Phosphatidylinositol 3-Kinase