Gibbs Energy of Superoxide Dismutase Heterodimerization Accounts for Variable Survival in Amyotrophic Lateral Sclerosis
| Autor: | Alireza Abdolvahabi, Mark J. Acerson, Yunhua Shi, Bryan F. Shaw, Richard A. Mowery |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Variable survival Protein subunit Mutant SOD1 medicine.disease_cause Biochemistry Catalysis Superoxide dismutase 03 medical and health sciences Colloid and Surface Chemistry Superoxide Dismutase-1 Internal medicine Enzyme Stability medicine Humans Amyotrophic lateral sclerosis Mutation biology Calorimetry Differential Scanning Chemistry Amyotrophic Lateral Sclerosis Half-life Electrophoresis Capillary General Chemistry medicine.disease 030104 developmental biology Endocrinology biology.protein Thermodynamics Protein Multimerization Half-Life |
| Zdroj: | Journal of the American Chemical Society. 138(16) |
| ISSN: | 1520-5126 |
| Popis: | The exchange of subunits between homodimeric mutant Cu, Zn superoxide dismutase (SOD1) and wild-type (WT) SOD1 is suspected to be a crucial step in the onset and progression of amyotrophic lateral sclerosis (ALS). The rate, mechanism, and ΔG of heterodimerization (ΔGHet) all remain undetermined, due to analytical challenges in measuring heterodimerization. This study used capillary zone electrophoresis to measure rates of heterodimerization and ΔGHet for seven ALS-variant apo-SOD1 proteins that are clinically diverse, producing mean survival times between 2 and 12 years (postdiagnosis). The ΔGHet of each ALS variant SOD1 correlated with patient survival time after diagnosis (R(2) = 0.98), with more favorable ΔGHet correlating with shorter survival by 4.8 years per kJ. Rates of heterodimerization did not correlate with survival time or age of disease onset. Metalation diminished the rate of subunit exchange by up to ∼38-fold but only altered ΔGHet by1 kJ mol(-1). Medicinal targeting of heterodimer thermodynamics represents a plausible strategy for prolonging life in SOD1-linked ALS. |
| Databáze: | OpenAIRE |
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