Structural Characterization of Zinc-deficient Human Superoxide Dismutase and Implications for ALS

摘要: Over 130 mutations to copper, zinc superoxide dismutase (SOD) are implicated in the selective death of motor neurons found 25% patients with familial amyotrophic lateral sclerosis (ALS). Despite their widespread distribution, ALS appear positioned cause structural and misfolding defects. Such defects decrease SOD's affinity for zinc, loss from SOD is sufficient induce apoptosis vitro. To examine importance site structure pathogenesis human SOD, we determined 2.0-A-resolution crystal a designed zinc-deficient which two zinc-binding ligands have been mutated hydrogen-bonding serine residues. This revealed 9 degrees twist subunits, opens dimer interface represents largest intersubunit rotational shift observed variant. Furthermore, electrostatic loop subloop were partly disordered, catalytically important Arg143 was rotated away active site, normally rigid intramolecular Cys57-Cys146 disulfide bridge assumed conformations. Together, these changes allow small molecules greater access catalytic consistent increased redox activity SOD. Moreover, weakened more labile, as demonstrated by aggregation presence thiol reductant. However, equimolar Cu,Zn rapidly forms heterodimers (t1/2 approximately 15 min) prevents aggregation. The stabilization heterodimer may contribute dominant inheritance mutations. These results general implications framework stability on normal metalloenzyme function specific role ion fatal neuropathology associated