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Sequence and structural determinants of Cu, Zn superoxide dismutase aggregation
Sagar D Khare1, Kyle C Wilcox, Peng Gong
1Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Proteins
|September 10, 2005
Summary
Mutations in copper-zinc superoxide dismutase (SOD1) cause familial amyotrophic lateral sclerosis by destabilizing the protein. This study identifies aggregation-prone regions in SOD1, revealing key structural factors contributing to disease.
Area of Science:
- Biochemistry
- Structural Biology
- Neuroscience
Background:
- Familial amyotrophic lateral sclerosis (ALS) is linked to mutations in Cu, Zn superoxide dismutase (SOD1).
- Mutant SOD1 destabilizes, leading to protein aggregation, but the structural basis remains unclear.
Purpose of the Study:
- Investigate the sequence and structural determinants of SOD1 aggregation in silico.
- Identify specific protein regions prone to aggregation and intermolecular interactions.
Main Methods:
- Sequence analysis to identify aggregation-prone fragments.
- Molecular dynamics simulations of SOD1 dimer folding and misfolding.
Main Results:
- Identified identical regions (N- and C-termini, crossover loops, beta-strands) with high aggregation propensity using both sequence and simulation methods.
- These regions are predisposed to intermolecular interactions.
Conclusions:
- SOD1 aggregation propensity arises from a synergy between inherently amyloidogenic sequence fragments and their structural context.
- The balance between self-association of prone sequences and structural context dictates protein aggregation.