Human mitochondrial manganese superoxide dismutase polymorphic variant Ile58Thr reduces activity by destabilizing the tetrameric interface

Journal Article · Tue Apr 09 04:00:00 EDT 1996 · Biochemistry (Eaton)

DOI:https://doi.org/10.1021/bi951892w· OSTI ID:508208

Borgstahl, G E.O.; Hickey, M J; Johnson, M J ^[1]

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1. Scripps Research Institute, La Jolla, CA (United States); and others

Human manganese superoxide dismutase (MnSOD) is a homotetrameric enzyme which protects mitochondria against oxygen-mediated free radical damage. Within each subunit, both the N-terminal helical hairpin and C-terminal {alpha}/{beta} domains contribute ligands to the catalytic manganese site. Two identical four-helix bundles,symmetrically assembled form the N-terminal helical hairpins, form a novel tetrameric interface that stabilizes the active sites. The 2.5 {angstrom} crystallographic structure of the naturally occurring polymorphic variant Ile58Thr MnSOD reveals that the helical hairpin mutation Thr58 causes two packing defects in each of the two four-helix bundles of the tetrameric interface. Similar mutations, expected to cause packing defects in the Cu,ZnSOD dimer interface, are associated with the degenerative disease amyotrophic lateral sclerosis. Ile58Thr MnSOD is primarily dimeric in solution and is significantly less thermostable than the normal enzyme, with decreases of 15{degrees}C in the main melting temperature and 20{degrees}C in the heat-inactivation temperature. Consequently, this mutant MnSOD is compromised at normal body temperatures: thermal inactivation, predicted from the decrease in thermal stability, occurs with a theoretical half-life of only 3.2h at 37{degrees}C (1.4 h at 41 {degrees}C), compared with 3.1 years for native MnSOD. This prediction is supported by direct measurements: incubation at 41.7{degrees}C for 3 h has no effect on the activity of native MnSOD but completely inactivates mutant MnSOD. Rapid inactivation of Ile58Thr MnSOD at the elevated temperatures associated with fever and inflammation could provide an early advantage by killing infected cells, but also would increase superoxide-mediated oxidative damage and perhaps contribute to late-onset diseases. 63 refs., 7 figs., 2 tabs.

• OSTI ID: 508208
• Journal Information: Biochemistry (Eaton), Journal Name: Biochemistry (Eaton) Journal Issue: 14 Vol. 35; ISSN 0006-2960; ISSN BICHAW
• Country of Publication: United States
• Language: English

Related Subjects

55 BIOLOGY AND MEDICINE
BASIC STUDIES
CRYSTAL STRUCTURE
ENZYME ACTIVITY
INFLAMMATION
LIGANDS
MANGANESE COMPOUNDS
MITOCHONDRIA
MUTATIONS
NERVOUS SYSTEM DISEASES
STABILITY
SUPEROXIDE DISMUTASE
TEMPERATURE DEPENDENCE
THREONINE