Abstract:
:The molecular mechanism by which the homodimeric enzyme Cu/Zn superoxide dismutase (SOD) causes neural damage in amytrophic lateral sclerosis is yet poorly understood. A striking, as well as an unusual, feature of SOD is that it maintains intrasubunit disulfide bonds in the reducing environment of the cytosol. Here, we investigate the role of these disulfide bonds in folding and assembly of the SOD apo protein (apoSOD) homodimer through extensive protein engineering. The results show that apoSOD folds in a simple three-state process by means of two kinetic barriers: 2D<==>2M<==>M(2). The early predominant barrier represents folding of the monomers (M), and the late barrier the assembly of the dimer (M(2)). Unique for this mechanism is a dependence of protein concentration on the unfolding rate constant under physiological conditions, which disappears above 6 M Urea where the transition state for unfolding shifts to first-order dissociation of the dimer in accordance with Hammond-postulate behavior. Although reduction of the intrasubunit disulfide bond C57-C146 is not critical for folding of the apoSOD monomer, it has a pronounced effect on its stability and abolishes subsequent dimerization. Thus, impaired ability to form, or retain, the C57-C146 bond in vivo is predicted to increase the cellular load of marginally stable apoSOD monomers, which may have implications for the amytrophic lateral sclerosis neuropathology.
journal_name
Proc Natl Acad Sci U S Aauthors
Lindberg MJ,Normark J,Holmgren A,Oliveberg Mdoi
10.1073/pnas.0403979101keywords:
subject
Has Abstractpub_date
2004-11-09 00:00:00pages
15893-8issue
45eissn
0027-8424issn
1091-6490pii
0403979101journal_volume
101pub_type
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