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Functional features cause misfolding of the ALS-provoking enzyme SOD1
Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden.
Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden.
Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden. (Department of Molecular Biophysics, Lund University, S-221 00 Lund, Sweden)
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
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2009 (Engelska)Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, nr 24, s. 9667-9672Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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 Zn2+ 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 Zn2+ ion with μM 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 Zn2+ 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.

Ort, förlag, år, upplaga, sidor
National Academy of Sciences , 2009. Vol. 106, nr 24, s. 9667-9672
Nyckelord [en]
functional evolution, protein disease, protein misfolding
Nationell ämneskategori
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
Identifikatorer
URN: urn:nbn:se:umu:diva-23183DOI: 10.1073/pnas.0812046106OAI: oai:DiVA.org:umu-23183DiVA, id: diva2:220934
Tillgänglig från: 2009-06-03 Skapad: 2009-06-03 Senast uppdaterad: 2018-06-08Bibliografiskt granskad

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Gröbner, GerhardZetterström, Per

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Gröbner, GerhardZetterström, Per
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Kemiska institutionenInstitutionen för medicinsk biovetenskap
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Proceedings of the National Academy of Sciences of the United States of America
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)

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