Structural Changes to Monomeric CuZn Superoxide Dismutase Caused by the Familial Amyotrophic Lateral Sclerosis-Associated Mutation A4V
| Autor: | Tom Schmidlin, Valerie Daggett, Brian K. Kennedy |
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| Jazyk: | angličtina |
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Models
Molecular Protein Folding Time Factors SOD1 Mutant Biophysics 010402 general chemistry medicine.disease_cause 01 natural sciences Superoxide dismutase 03 medical and health sciences Protein structure Apoenzymes Superoxide Dismutase-1 Mutant protein Enzyme Stability medicine Humans Amyotrophic lateral sclerosis Protein Structure Quaternary 030304 developmental biology Genetics 0303 health sciences Mutation Binding Sites biology Chemistry Superoxide Dismutase Point mutation Protein Amyotrophic Lateral Sclerosis medicine.disease 0104 chemical sciences Cell biology Zinc biology.protein Disease Progression Mutant Proteins Protein Multimerization Copper |
| Zdroj: | Biophysical Journal. (6):1709-1718 |
| ISSN: | 0006-3495 |
| DOI: | 10.1016/j.bpj.2009.06.043 |
| Popis: | Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron degenerative disease, and the inherited form, familial ALS (fALS), has been linked to over 100 different point mutations scattered throughout the Cu-Zn superoxide dismutase protein (SOD1). The disease is likely due to a toxic gain of function caused by the misfolding, oligomerization, and eventual aggregation of mutant SOD1, but it is not yet understood how the structurally diverse mutations result in a common disease phenotype. The behavior of the apo-monomer fALS-associated mutant protein A4V was explored using molecular-dynamics simulations to elucidate characteristic structural changes to the protein that may allow the mutant form to improperly associate with other monomer subunits. Simulations showed that the mutant protein is less stable than the WT protein overall, with shifts in residue-residue contacts that lead to destabilization of the dimer and metal-binding sites, and stabilization of nonnative contacts that leads to a misfolded state. These findings provide a unifying explanation for disparate experimental observations, allow a better understanding of alterations of residue contacts that accompany loss of SOD1 structural integrity, and suggest sites where compensatory changes may stabilize the mutant structure. |
| Databáze: | OpenAIRE |
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