Amyotrophic Lateral Sclerosis and Structural Defects in Cu,Zn Superoxide Dismutase

Single-site mutants in the Cu,Zn superoxide dismutase (SOD) gene (SOD1) occur in patients with the fatal neurodegenerative disorder familial amyotrophic lateral sclerosis (FALS). Complete screening of the SOD1 coding region revealed that the mutation Ala$^4$ to Val in exon 1 was the most frequent on...

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Published in:Science (American Association for the Advancement of Science) 1993-08, Vol.261 (5124), p.1047-1051
Main Authors: Deng, Han-Xiang, Hentati, Afif, Tainer, John A., Iqbal, Zafar, Cayabyab, Annarueber, Hung, Wu-Yen, Getzoff, Elizabeth D., Hu, Ping, Herzfeldt, Brian, Roos, Raymond P., Warner, Carolyn, Deng, Gang, Soriano, Edwin, Smyth, Celestine, Parge, Hans E., Ahmed, Aftab, Roses, Allen D., Hallewell, Robert A., Pericak-Vance, Margaret A., Siddique, Teepu
Format: Article
Language:English
Subjects:
Active sites
Amino Acid Sequence
Amyotrophic lateral sclerosis
Amyotrophic Lateral Sclerosis - enzymology
Amyotrophic Lateral Sclerosis - genetics
Base Sequence
Binding Sites
Biological and medical sciences
cell death
copper
crystal structure
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Dimers
DNA
Enzymes
Erythrocytes - enzymology
Exons
Free radicals
Free Radicals - metabolism
genes
Genetic mutation
Humans
man
Medical sciences
Models, Molecular
Molecular Sequence Data
motor neurons
Mutation
Neurology
Protein Folding
Protein Structure, Tertiary
superoxide dismutase
Superoxide Dismutase - blood
Superoxide Dismutase - chemistry
Superoxide Dismutase - genetics
Superoxide Dismutase - metabolism
Superoxides
X-Ray Diffraction
zinc
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Summary:Single-site mutants in the Cu,Zn superoxide dismutase (SOD) gene (SOD1) occur in patients with the fatal neurodegenerative disorder familial amyotrophic lateral sclerosis (FALS). Complete screening of the SOD1 coding region revealed that the mutation Ala$^4$ to Val in exon 1 was the most frequent one; mutations were identified in exons 2, 4, and 5 but not in the active site region formed by exon 3. The 2.4 $\angst $ crystal structure of human SOD, along with two other SOD structures, established that all 12 observed FALS mutant sites alter conserved interactions critical to the β-barrel fold and dimer contact, rather than catalysis. Red cells from heterozygotes had less than 50 percent normal SOD activity, consistent with a structurally defective SOD dimer. Thus, defective SOD is linked to motor neuron death and carries implications for understanding and possible treatment of FALS.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.8351519