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Contribution of disulfide bonds to stability, folding, and amyloid fibril formation: the PI3-SH3 domain case.
- Source :
-
Antioxidants & redox signaling [Antioxid Redox Signal] 2012 Jan 01; Vol. 16 (1), pp. 1-15. Date of Electronic Publication: 2011 Sep 15. - Publication Year :
- 2012
-
Abstract
- Aims: 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.<br />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.<br />Innovation: 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.<br />Conclusion: Disulfide bridges may act as key molecular determinants of both productive protein folding and deleterious aggregation reactions.
- Subjects :
- Amino Acid Sequence
Amyloid metabolism
Animals
Cattle
Hydrogen-Ion Concentration
Kinetics
Models, Molecular
Molecular Sequence Data
Nuclear Magnetic Resonance, Biomolecular
Oxidation-Reduction
Protein Conformation
Protein Denaturation
Protein Folding
Protein Stability
Thermodynamics
Amyloid chemistry
Class Ia Phosphatidylinositol 3-Kinase chemistry
src Homology Domains
Subjects
Details
- Language :
- English
- ISSN :
- 1557-7716
- Volume :
- 16
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Antioxidants & redox signaling
- Publication Type :
- Academic Journal
- Accession number :
- 21797671
- Full Text :
- https://doi.org/10.1089/ars.2011.3936