The copper-iron connection in biology: structure of the metallo-oxidase Fet3p.
Fet3p is a multicopper-containing glycoprotein localized to the yeast plasma membrane that catalyzes the oxidation of Fe(II) to Fe(III). This ferrous iron oxidation is coupled to the reduction of O(2) to H(2)O and is termed the ferroxidase reaction. Fet3p-produced Fe(III) is transferred to the permease Ftr1p for import into the cytosol. The posttranslational insertion of four copper ions into Fet3p is essential for its activity, thus linking copper and iron homeostasis. The mammalian ferroxidases ceruloplasmin and hephaestin are homologs of Fet3p. Loss of the Fe(II) oxidation catalyzed by these proteins results in a spectrum of pathological states, including death. Here, we present the structure of the Fet3p extracellular ferroxidase domain and compare it with that of human ceruloplasmin and other multicopper oxidases that are devoid of ferroxidase activity. The Fet3p structure delineates features that underlie the unique reactivity of this and homologous multicopper oxidases that support the essential trafficking of iron in diverse eukaryotic organisms. The findings are correlated with biochemical and physiological data to cross-validate the elements of Fet3p that define it as both a ferroxidase and cuprous oxidase.
Taylor
Alexander B
AB
Department of Biochemistry and the X-Ray Crystallography Core Laboratory, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
Stoj
Christopher S
CS
Ziegler
Lynn
L
Kosman
Daniel J
DJ
Hart
P John
PJ
D002570:Ceruloplasmin / Q000737:chemistry* / Q000502:physiology; D003300:Copper / Q000737:chemistry; D007501:Iron / Q000378:metabolism; D042845:Laccase / Q000737:chemistry; D017510:Protein Folding; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000502:physiology
D029701:Saccharomyces cerevisiae Proteins; D003300:Copper; D007501:Iron; D042845:Laccase; D002570:Ceruloplasmin; C085513:FET3 protein, S cerevisiae