MF2100014 Superoxide dismutase (SOD) 2c9v X-ray 1.07 Homodimer Homo sapiens 16406071 Strange RW, Antonyuk SV, Hough MA, Doucette PA, Valentine JS, Hasnain SS J. Mol. Biol. 2006 5 356 1152-62 Human Cu-Zn superoxide dismutase (SOD1) protects cells from the effects of oxidative stress. Mutations in SOD1 are linked to the familial form of amyotrophic lateral sclerosis. Several hypotheses for their toxicity involve the mis-metallation of the enzyme. We present atomic-resolution crystal structures and biophysical data for human SOD1 in three metallation states: Zn-Zn, Cu-Zn and as-isolated. These data represent the first atomic-resolution structures for human SOD1, the first structure of a reduced SOD1, and the first structure of a fully Zn-substituted SOD1 enzyme. Recombinantly expressed as-isolated SOD1 contains a mixture of Zn and Cu at the Cu-binding site. The Zn-Zn structure appears to be at least as stable as the correctly (Cu-Zn) metallated enzyme. These data raise the possibility that in a cellular environment with low availability of free copper, Zn-Zn may be the preferred metallation state of SOD1 prior to its interaction with the copper chaperone. GO:0005507 copper ion binding GO:0042802 identical protein binding GO:0030346 protein phosphatase 2B binding GO:0051087 protein-folding chaperone binding GO:0031267 small GTPase binding GO:0004784 superoxide dismutase activity GO:0008270 zinc ion binding GO:1904115 axon cytoplasm GO:0005737 cytoplasm GO:0031410 cytoplasmic vesicle GO:0005829 cytosol GO:0032839 dendrite cytoplasm GO:0070062 extracellular exosome GO:0005576 extracellular region GO:0005615 extracellular space GO:0005758 mitochondrial intermembrane space GO:0005759 mitochondrial matrix GO:0005739 mitochondrion GO:0043025 neuronal cell body GO:0005654 nucleoplasm GO:0005634 nucleus GO:0005777 peroxisome GO:0032991 protein-containing complex GO:0099610 action potential initiation GO:0008089 anterograde axonal transport GO:0006915 apoptotic process GO:0060088 auditory receptor cell stereocilium organization GO:0008340 determination of adult lifespan GO:0035234 ectopic germ cell programmed cell death GO:0007566 embryo implantation GO:0010467 gene expression GO:0006749 glutathione metabolic process GO:0060047 heart contraction GO:0050665 hydrogen peroxide biosynthetic process GO:0006879 intracellular iron ion homeostasis GO:0007626 locomotory behavior GO:0046716 muscle cell cellular homeostasis GO:0002262 myeloid cell homeostasis GO:0045541 negative regulation of cholesterol biosynthetic process GO:0051093 negative regulation of developmental process GO:0050728 negative regulation of inflammatory response GO:0043524 negative regulation of neuron apoptotic process GO:2000242 negative regulation of reproductive process GO:0060052 neurofilament cytoskeleton organization GO:0019228 neuronal action potential GO:0001541 ovarian follicle development GO:0032287 peripheral nervous system myelin maintenance GO:0001890 placenta development GO:0043065 positive regulation of apoptotic process GO:0043085 positive regulation of catalytic activity GO:0001819 positive regulation of cytokine production GO:0043410 positive regulation of MAPK cascade GO:1902177 positive regulation of oxidative stress-induced intrinsic apoptotic signaling pathway GO:0050766 positive regulation of phagocytosis GO:0032930 positive regulation of superoxide anion generation GO:0072593 reactive oxygen species metabolic process GO:0008217 regulation of blood pressure GO:0043087 regulation of GTPase activity GO:0051881 regulation of mitochondrial membrane potential GO:0040014 regulation of multicellular organism growth GO:0046620 regulation of organ growth GO:0045859 regulation of protein kinase activity GO:0033081 regulation of T cell differentiation in thymus GO:0060087 relaxation of vascular associated smooth muscle GO:0019430 removal of superoxide radicals GO:0048678 response to axon injury GO:0045471 response to ethanol GO:0009408 response to heat GO:0042542 response to hydrogen peroxide GO:0010033 response to organic substance GO:0000303 response to superoxide GO:0009410 response to xenobiotic stimulus GO:0001895 retina homeostasis GO:0008090 retrograde axonal transport GO:0007605 sensory perception of sound GO:0007283 spermatogenesis GO:0042554 superoxide anion generation GO:0006801 superoxide metabolic process GO:0048538 thymus development GO:0019226 transmission of nerve impulse 2 1 Homooligomeric enzymes Homodimeric enzymes All chains according to the most probable oligomerization state stored in PDBe were considered. A Superoxide dismutase [Cu-Zn] Homo sapiens P00441 2 154 99% MATKAVCVLKGDGPVQGIINFEQKESNGPVKVWGSIKGLTEGLHGFHVHEFGDNTAGCTSAGPHFNPLSRKHGGPKDEERHVGDLGNVTADKDGVADVSIEDSVISLSGDHCIIGRTLVVHEKADDLGKGGNEESTKTGNAGSRLACGVIGIAQ 154 secondary structure helix 55 61 secondary structure helix 107 110 secondary structure helix 131 136 secondary structure strand 2 8 secondary structure strand 15 22 secondary structure strand 29 36 secondary structure strand 41 48 secondary structure strand 83 89 secondary structure strand 95 101 secondary structure strand 116 120 secondary structure strand 143 148 secondary structure strand 150 151 pfam PF00080 Copper/zinc superoxide dismutase (SODC) 15 150 F Superoxide dismutase [Cu-Zn] Homo sapiens P00441 2 154 99% MATKAVCVLKGDGPVQGIINFEQKESNGPVKVWGSIKGLTEGLHGFHVHEFGDNTAGCTSAGPHFNPLSRKHGGPKDEERHVGDLGNVTADKDGVADVSIEDSVISLSGDHCIIGRTLVVHEKADDLGKGGNEESTKTGNAGSRLACGVIGIAQ 154 secondary structure helix 55 61 secondary structure helix 133 138 secondary structure strand 3 10 secondary structure strand 14 22 secondary structure strand 29 36 secondary structure strand 41 48 secondary structure strand 83 89 secondary structure strand 95 101 secondary structure strand 116 120 secondary structure strand 143 148 secondary structure strand 150 151 pfam PF00080 Copper/zinc superoxide dismutase (SODC) 15 150 Direct evidence The full structure participates in mutual synergistic folding. - CD measurements and a global analysis decomposition of the time-resolved fluorescence decay over denaturant concentration shows the presence of an intermediate in the unfolding of human SOD by guanidinium hydrochloride. Considering previous measurements of partially denatured HSOD as a function of protein concentration (PMID:1510915), these results strongly suggest that the unfolding intermediate is a monomer that displays a molten globule state (PMID:8298055). A N/A F N/A