1N18

Thermostable mutant of Human Superoxide Dismutase, C6A, C111S

Summary for 1N18

• Entry DOI: 10.2210/pdb1n18/pdb
• Related: 1M19
• Descriptor: Superoxide dismutase [Cu-Zn], COPPER (I) ION, ZINC ION, ... (5 entities in total)
• Functional Keywords: greek key beta barrel, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P00441
• Total number of polymer chains: 10
• Total formula weight: 160491.89

Authors

Cardoso, R.M.F.,Thayer, M.M.,DiDonato, M.,Lo, T.P.,Bruns, C.K.,Getzoff, E.D.,Tainer, J.A. (deposition date: 2002-10-16, release date: 2002-11-27, Last modification date: 2024-11-20)

Primary citation

Cardoso, R.M.F.,Thayer, M.M.,DiDonato, M.,Lo, T.P.,Bruns, C.K.,Getzoff, E.D.,Tainer, J.A.
Insights into Lou Gehrig's disease from the structure and instability of the A4V mutant of human Cu,Zn superoxide dismutase.
J.Mol.Biol., 324:247-256, 2002

PubMed Abstract: Mutations in human superoxide dismutase (HSOD) have been linked to the familial form of amyotrophic lateral sclerosis (FALS). Amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) is one of the most common neurodegenerative disorders in humans. In ALS patients, selective killing of motor neurons leads to progressive paralysis and death within one to five years of onset. The most frequent FALS mutation in HSOD, Ala4-->Val, is associated with the most rapid disease progression. Here we identify and characterize key differences in the stability between the A4V mutant protein and its thermostable parent (HSOD-AS), in which free cysteine residues were mutated to eliminate interferences from cysteine oxidation. Denaturation studies reveal that A4V unfolds at a guanidine-HCl concentration 1M lower than HSOD-AS, revealing that A4V is significantly less stable than HSOD-AS. Determination and analysis of the crystallographic structures of A4V and HSOD-AS reveal structural features likely responsible for the loss of architectural stability of A4V observed in the denaturation experiments. The combined structural and biophysical results presented here argue that architectural destabilization of the HSOD protein may underlie the toxic function of the many HSOD FALS mutations.

PubMed: 12441104
DOI: 10.1016/S0022-2836(02)01090-2

Experimental method

X-RAY DIFFRACTION (2 Å)