| Autor: |
Zhang B; Department of Biological Sciences, The University of Texas at Dallas, Richardson, Texas 75083, United States., Boyd SD; Department of Biological Sciences, The University of Texas at Dallas, Richardson, Texas 75083, United States., Zhabilov D; Department of Biological Sciences, The University of Texas at Dallas, Richardson, Texas 75083, United States., Ullrich M; Department of Biological Sciences, The University of Texas at Dallas, Richardson, Texas 75083, United States., Blackburn NJ; Department of Chemical Physiology and Biochemistry, Oregon Health and Sciences University, Portland, Oregon 97239, United States., Winkler DD; Department of Biological Sciences, The University of Texas at Dallas, Richardson, Texas 75083, United States. |
| Abstrakt: |
The copper chaperone for Sod1 (Ccs) is a metallochaperone that plays a multifaceted role in the maturation of Cu,Zn superoxide dismutase (Sod1). The Ccs mutation R 163 W was identified in an infant with fatal neurological abnormalities. Based on a comprehensive structural and functional analysis, we developed the first data-driven model for R 163 W-related pathogenic phenotypes. The work here confirms previous findings that the substitution of arginine with tryptophan at this site, which is located adjacent to a conserved Zn binding site, creates an unstable Zn-deficient protein that loses its ability to efficiently activate Sod1. Intriguingly, R 163 W Ccs can reduce copper (i.e., Cu(II) → Cu(I)) bound in its Sod1-like domain (D2), and this novel redox event is accompanied by disulfide bond formation. The loss of Zn binding, along with the unusual ability to bind copper in D2, diverts R 163 W Ccs toward aggregation. The remarkably high affinity of D2 Cu(I) binding converts R 163 W from a Cu chaperone to a Cu scavenger that accelerates Sod1 deactivation (i.e., an Anti-chaperone). Overall, these findings present a first-of-its-kind molecular mechanism for Ccs dysfunction that leads to pathogenesis in humans. |
