Posttranslational modifications in Cu,Zn-superoxide dismutase and mutations associated with amyptrophic lateral sclerosis

Yoshiaki Furukawa, Thomas V. O'Halloran

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

Activation of the enzyme Cu,Zn-superoxide dismutase (SOD1) involves several posttranslational modifications including copper and zinc binding, as well as formation of the intramolecular disulfide bond. The copper chaperone for SOD1, CCS, is responsible for intracellular copper loading in SOD1 under most physiological conditions. Recent in vitro and in vivo assays reveal that CCS not only delivers copper to SOD1 under stringent copper limitation, but it also facilitates the stepwise conversion of the disulfide-reduced immature SOD1 to the active disulfide-containing enzyme. The two new functions attributed to CCS, (i.e., O2-dependent sulfhydryl oxidase- and disulfide isomerase-like activities) indicate that this protein has attributes of the larger class of molecular chaperones. The CCS-dependent activation of SOD1 is dependent upon oxygen availability, suggesting that the cell only loads copper and activates this enzyme when O2-based oxidative stress is present. Thiol/disulfide status as well as metallation state of SOD1 significantly affects its structure and protein aggregation, which are relevant in pathologies of a neurodegenerative disease, amyotrophic lateral sclerosis (ALS). The authors review here a mechanism for posttranslational activation of SOD1 and discuss models for ALS in which the most immature forms of the SOD1 polypeptide exhibits propensity to form toxic aggregates.

Original languageEnglish
Pages (from-to)847-867
Number of pages21
JournalAntioxidants and Redox Signaling
Volume8
Issue number5-6
DOIs
Publication statusPublished - 2006 May
Externally publishedYes

Fingerprint

Motor Neuron Disease
Post Translational Protein Processing
Copper
Disulfides
Mutation
Chemical activation
Amyotrophic Lateral Sclerosis
Enzymes
Neurodegenerative diseases
Protein Disulfide-Isomerases
Molecular Chaperones
Enzyme Activation
Oxidative stress
Poisons
Pathology
Sulfhydryl Compounds
Neurodegenerative Diseases
Superoxide Dismutase-1
Superoxide Dismutase
Zinc

ASJC Scopus subject areas

  • Biochemistry

Cite this

Posttranslational modifications in Cu,Zn-superoxide dismutase and mutations associated with amyptrophic lateral sclerosis. / Furukawa, Yoshiaki; O'Halloran, Thomas V.

In: Antioxidants and Redox Signaling, Vol. 8, No. 5-6, 05.2006, p. 847-867.

Research output: Contribution to journalArticle

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