3HFF

Monomeric human Cu,Zn Superoxide dismutase without Zn ligands

Summary for 3HFF

• Entry DOI: 10.2210/pdb3hff/pdb
• Descriptor: Superoxide dismutase [Cu-Zn], ZINC ION (3 entities in total)
• Functional Keywords: oxidoreductase, sod1, monomeric mutant, amyotrophic lateral sclerosis, antioxidant, disease mutation, disulfide bond, metal-binding, neurodegeneration, phosphoprotein
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : P00441
• Total number of polymer chains: 1
• Total formula weight: 15963.26

Authors

Saraboji, K.,Nordlund, A.,Leinartait, L.,Oliveberg, M.,Logan, D.T. (deposition date: 2009-05-11, release date: 2009-06-16, Last modification date: 2024-05-29)

Primary citation

Nordlund, A.,Leinartaite, L.,Saraboji, K.,Aisenbrey, C.,Grobner, G.,Zetterstrom, P.,Danielsson, J.,Logan, D.T.,Oliveberg, M.
Functional features cause misfolding of the ALS-provoking enzyme SOD1.
Proc.Natl.Acad.Sci.USA, 106:9667-9672, 2009

PubMed Abstract: The structural integrity of the ubiquitous enzyme superoxide dismutase (SOD1) relies critically on the correct coordination of Cu and Zn. Loss of these cofactors not only promotes SOD1 aggregation in vitro but also seems to be a key prerequisite for pathogenic misfolding in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We examine here the consequences of Zn(2+) loss by selectively removing the Zn site, which has been implicated as the main modulator of SOD1 stability and disease competence. After Zn-site removal, the remaining Cu ligands can coordinate a nonnative Zn(2+) ion with microM affinity in the denatured state, and then retain this ion throughout the folding reaction. Without the restriction of a metallated Zn site, however, the Cu ligands fail to correctly coordinate the nonnative Zn(2+) ion: Trapping of a water molecule causes H48 to change rotamer and swing outwards. The misligation is sterically incompatible with the native structure. As a consequence, SOD1 unfolds locally and interacts with neighboring molecules in the crystal lattice. The findings point to a critical role for the native Zn site in controlling SOD1 misfolding, and show that even subtle changes of the metal-loading sequence can render the wild-type protein the same structural properties as ALS-provoking mutations. This frustrated character of the SOD1 molecule seems to arise from a compromise between optimization of functional and structural features.

PubMed: 19497878
DOI: 10.1073/pnas.0812046106

Experimental method

X-RAY DIFFRACTION (2.2 Å)