Structural Instability and Cu-Dependent Pro-Oxidant Activity Acquired by the Apo Form of Mutant SOD1 Associated with Amyotrophic Lateral Sclerosis
| Autor: | Hirotsugu Hiramatsu, Nobuhiro Fujimaki, Furi Kitamura, Wakana Okita, Hideo Takeuchi |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Antioxidant medicine.medical_treatment SOD1 medicine.disease_cause Biochemistry Protein Structure Secondary Structure-Activity Relationship Superoxide Dismutase-1 Enzyme Stability medicine Humans Amyotrophic lateral sclerosis Protein Structure Quaternary chemistry.chemical_classification Mutation Superoxide Dismutase Circular Dichroism Amyotrophic Lateral Sclerosis medicine.disease Pro-oxidant Molecular biology Cytosol Enzyme chemistry Disease Progression Mutant Proteins Dismutase Protein Multimerization Apoproteins Reactive Oxygen Species Copper |
| Zdroj: | Biochemistry. 50:4242-4250 |
| ISSN: | 1520-4995 0006-2960 |
| DOI: | 10.1021/bi200338h |
| Popis: | Cu,Zn-superoxide dismutase (SOD1) is a cytosolic antioxidant enzyme, and its mutation has been implicated in amyotrophic lateral sclerosis (ALS), a disease causing a progressive loss of motor neurons. Although the pathogenic mechanism of ALS remains unclear, it is hypothesized that some toxic properties acquired by mutant SOD1 play a role in the development of ALS. We have examined the structural and catalytic properties of an ALS-linked mutant of human SOD1, His43Arg (H43R), which is characterized by rapid disease progression. As revealed by circular dichroism spectroscopy, H43R assumes a stable β-barrel structure in the Cu(2+),Zn(2+)-bound holo form, but its metal-depleted apo form is highly unstable and readily unfolds or misfolds into an irregular structure at physiological temperature. The conformational change occurs as a two-state transition from a nativelike apo form to a denatured apo form with a half-life of ∼0.5 h. At the same time as the denaturation, the apo form of H43R acquires pro-oxidant potential, which is fully expressed in the presence of Cu(2+) and H(2)O(2), as monitored with a fluorogenic probe for detecting pro-oxidant activity. Comparison of d-d absorption bands suggests that the Cu(2+) binding mode of the denatured apo form is different from that of the native holo form. The denatured apo form of H43R is likely to provide non-native Cu(2+) binding sites where the Cu(2+) ion is activated to catalyze harmful oxidation reactions. This study raises the possibility that the structural instability and the resultant Cu-dependent pro-oxidant activity of the apo form of mutant SOD1 may be one of the pathogenic mechanisms of ALS. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|