1PTZ

Crystal structure of the human CU, Zn Superoxide Dismutase, Familial Amyotrophic Lateral Sclerosis (FALS) Mutant H43R

Summary for 1PTZ

• Entry DOI: 10.2210/pdb1ptz/pdb
• Related: 1PU0
• Descriptor: Superoxide dismutase [Cu-Zn], COPPER (I) ION, ZINC ION, ... (5 entities in total)
• Functional Keywords: sod, fals mutant, amyotrophic lateral sclerosis, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P00441
• Total number of polymer chains: 2
• Total formula weight: 31950.93

Authors

DiDonato, M.,Craig, L.,Huff, M.E.,Thayer, M.M.,Cardoso, R.M.F.,Kassmann, C.J.,Lo, T.P.,Bruns, C.K.,Powers, E.T.,Kelly, J.W.,Getzoff, E.D.,Tainer, J.A. (deposition date: 2003-06-23, release date: 2003-09-09, Last modification date: 2024-10-30)

Primary citation

DiDonato, M.,Craig, L.,Huff, M.E.,Thayer, M.M.,Cardoso, R.M.F.,Kassmann, C.J.,Lo, T.P.,Bruns, C.K.,Powers, E.T.,Kelly, J.W.,Getzoff, E.D.,Tainer, J.A.
ALS Mutants of Human Superoxide Dismutase Form Fibrous Aggregates Via Framework Destabilization
J.Mol.Biol., 332:601-615, 2003

PubMed Abstract: Many point mutations in human Cu,Zn superoxide dismutase (SOD) cause familial amyotrophic lateral sclerosis (FALS), a fatal neurodegenerative disorder in heterozygotes. Here we show that these mutations cluster in protein regions influencing architectural integrity. Furthermore, crystal structures of SOD wild-type and FALS mutant H43R proteins uncover resulting local framework defects. Characterizations of beta-barrel (H43R) and dimer interface (A4V) FALS mutants reveal reduced stability and drastically increased aggregation propensity. Moreover, electron and atomic force microscopy indicate that these defects promote the formation of filamentous aggregates. The filaments resemble those seen in neurons of FALS patients and bind both Congo red and thioflavin T, suggesting the presence of amyloid-like, stacked beta-sheet interactions. These results support free-cysteine-independent aggregation of FALS mutant SOD as an integral part of FALS pathology. They furthermore provide a molecular basis for the single FALS disease phenotype resulting from mutations of diverse side-chains throughout the protein: many FALS mutations reduce structural integrity, lowering the energy barrier for fibrous aggregation.

PubMed: 12963370
DOI: 10.1016/S0022-2836(03)00889-1

Experimental method

X-RAY DIFFRACTION (1.8 Å)