DOI: 10.1073/pnas.0506227102. The copper-iron connection in biology: Structure of the metallo-oxidase Fet3p

The copper-iron connection in biology: Structure of the metallo-oxidase Fet3p

10.1073/pnas.0506227102

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

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.

Bibliography

Taylor, A. B., Stoj, C. S., Ziegler, L., Kosman, D. J., & Hart, P. J. (2005). The copper-iron connection in biology: Structure of the metallo-oxidase Fet3p. Proceedings of the National Academy of Sciences, 102(43), 15459â15464.

Authors 5

Alexander B. Taylor (first)
Christopher S. Stoj (additional)
Lynn Ziegler (additional)
Daniel J. Kosman (additional)
P. John Hart (additional)

References 64 Referenced 165

10.1182/blood.V7.11.1053.1053
10.1016/S0021-9258(18)38514-4
10.1016/S0021-9258(18)65051-3
10.3891/acta.chem.scand.02-0550
10.1002/pro.5560060402
Stoj C. S. & Kosman D. J. (2005) in Encyclopedia of Inorganic Chemistry ed. King R. B. (Wiley New York) pp. 1134-1159.
10.1021/cr950046o
10.1007/s007750050018
10.1016/S0021-9258(18)96527-0
10.1007/978-1-4684-3270-1_43
10.1146/annurev.nutr.22.012502.114457
10.1196/annals.1306.024
10.1126/science.271.5255.1552
10.1016/S0065-3233(02)60055-5
10.1046/j.1365-2958.2003.03368.x
10.1074/jbc.270.3.1098
10.1016/0092-8674(94)90345-X
10.1016/0092-8674(94)90346-8
10.1016/S0968-0004(98)01192-X
10.1023/A:1020771000746
10.1074/jbc.273.36.23274
10.1016/S0014-5793(03)01218-3
10.1007/s00775-003-0456-5
10.1074/jbc.M307019200
10.1016/S0076-6879(97)76068-3
10.1093/nar/28.1.235
10.1126/science.1925561
Otwinowski, Z. & Minor, W. (2001) in International Tables for Crystallography, eds. Rossman, M. & Arnold, E. (Kluwer, Dordrecht, The Netherlands), Vol. F, pp. 226-235. / International Tables for Crystallography (2001)
Evans P. (1993) in Proceedings of CCP4 Study Weekend on Data Collection and Processing eds. Sawyer L. Isaacs N. & Bailey S. (SERC Daresbury Laboratory Warrington U.K.) pp. 114-122.
10.1016/S0959-440X(99)00020-2
10.1016/0022-2836(68)90205-2
10.1107/S0907444998003254
10.1107/S0907444995008754
Kleywegt, G. J., Zou, J.-Y., Kjeldgaard, M. & Jones, T. A. (2001) in International Tables for Crystallography, eds. Rossman, M. & Arnold, E. (Kluwer, Dordrecht, The Netherlands), Vol. F, pp. 353-356, 366-368. / International Tables for Crystallography (2001)
10.1038/nsb0498-310
10.1016/0022-2836(92)90583-6
Hakulinen, N., Kiiskinen, L. L., Kruus, K., Saloheimo, M., Paananen, A., Koivula, A. & Rouvinen, J. (2002) Nat. Struct. Biol. 9, 601-605.12118243 / Nat. Struct. Biol. (2002)
10.1074/jbc.M204571200
10.1073/pnas.052710499
10.1006/jmbi.1993.1489
10.1107/S0108767386099622
10.1107/S0907444996012255
10.1107/S0907444900014736
10.1107/S0108767390010224
10.1107/S0907444904019158
DeLano W. L. (2002) pymol (DeLano Scientific San Carlos CA).
10.1006/jmbi.1993.1215
10.1021/bi992334a
10.1021/ja00255a032
10.1002/1521-3773(20011217)40:24<4570::AID-ANIE4570>3.0.CO;2-4
10.1021/ja003975s
10.1021/bi011979j
10.1007/s007750050156
10.1021/ja049220t
10.1021/bi0201318
10.1128/JB.186.22.7815-7817.2004
10.1074/jbc.M302963200
10.1021/ja010365z
10.1021/bi047379c
10.1074/jbc.273.35.22415
10.1016/S0014-5793(00)01435-6
10.1002/yea.1237
10.1021/ja00037a004
10.1042/bj20031921

Dates

Type	When
Created	19 years, 10 months ago (Oct. 17, 2005, 8:34 p.m.)
Deposited	3 years, 4 months ago (April 12, 2022, 2:04 p.m.)
Indexed	1 month, 3 weeks ago (July 14, 2025, 11:27 p.m.)
Issued	19 years, 10 months ago (Oct. 17, 2005)
Published	19 years, 10 months ago (Oct. 17, 2005)
Published Online	19 years, 10 months ago (Oct. 17, 2005)
Published Print	19 years, 10 months ago (Oct. 25, 2005)

Funders 0

None

BibTeX

@article{Taylor_2005, title={The copper-iron connection in biology: Structure of the metallo-oxidase Fet3p}, volume={102}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.0506227102}, DOI={10.1073/pnas.0506227102}, number={43}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Taylor, Alexander B. and Stoj, Christopher S. and Ziegler, Lynn and Kosman, Daniel J. and Hart, P. John}, year={2005}, month=oct, pages={15459–15464} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        7,
        15
      ]
    ],
    "date-time": "2025-07-15T03:27:45Z",
    "timestamp": 1752550065299
  },
  "reference-count": 64,
  "publisher": "Proceedings of the National Academy of Sciences",
  "issue": "43",
  "content-domain": {
    "domain": [
      "www.pnas.org"
    ],
    "crossmark-restriction": true
  },
  "published-print": {
    "date-parts": [
      [
        2005,
        10,
        25
      ]
    ]
  },
  "abstract": "<jats:p>\n            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\n            <jats:sub>2</jats:sub>\n            to H\n            <jats:sub>2</jats:sub>\n            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.\n          </jats:p>",
  "DOI": "10.1073/pnas.0506227102",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2005,
        10,
        18
      ]
    ],
    "date-time": "2005-10-18T00:34:14Z",
    "timestamp": 1129595654000
  },
  "page": "15459-15464",
  "update-policy": "http://dx.doi.org/10.1073/pnas.cm10313",
  "source": "Crossref",
  "is-referenced-by-count": 165,
  "title": "The copper-iron connection in biology: Structure of the metallo-oxidase Fet3p",
  "prefix": "10.1073",
  "volume": "102",
  "author": [
    {
      "given": "Alexander B.",
      "family": "Taylor",
      "sequence": "first",
      "affiliation": [
        {
          "name": "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; and Department of Biochemistry, School of Medicine and Biological Sciences, State University of New York, 140 Farber Hall, 3435 Main Street, Buffalo, NY 14214"
        }
      ]
    },
    {
      "given": "Christopher S.",
      "family": "Stoj",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "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; and Department of Biochemistry, School of Medicine and Biological Sciences, State University of New York, 140 Farber Hall, 3435 Main Street, Buffalo, NY 14214"
        }
      ]
    },
    {
      "given": "Lynn",
      "family": "Ziegler",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "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; and Department of Biochemistry, School of Medicine and Biological Sciences, State University of New York, 140 Farber Hall, 3435 Main Street, Buffalo, NY 14214"
        }
      ]
    },
    {
      "given": "Daniel J.",
      "family": "Kosman",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "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; and Department of Biochemistry, School of Medicine and Biological Sciences, State University of New York, 140 Farber Hall, 3435 Main Street, Buffalo, NY 14214"
        }
      ]
    },
    {
      "given": "P. John",
      "family": "Hart",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "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; and Department of Biochemistry, School of Medicine and Biological Sciences, State University of New York, 140 Farber Hall, 3435 Main Street, Buffalo, NY 14214"
        }
      ]
    }
  ],
  "member": "341",
  "published-online": {
    "date-parts": [
      [
        2005,
        10,
        17
      ]
    ]
  },
  "reference": [
    {
      "key": "e_1_3_2_1_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1182/blood.V7.11.1053.1053"
    },
    {
      "key": "e_1_3_2_2_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0021-9258(18)38514-4"
    },
    {
      "key": "e_1_3_2_3_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0021-9258(18)65051-3"
    },
    {
      "key": "e_1_3_2_4_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.3891/acta.chem.scand.02-0550"
    },
    {
      "key": "e_1_3_2_5_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/pro.5560060402"
    },
    {
      "key": "e_1_3_2_6_2",
      "unstructured": "Stoj C. S. & Kosman D. J. (2005) in Encyclopedia of Inorganic Chemistry ed. King R. B. (Wiley New York) pp. 1134-1159."
    },
    {
      "key": "e_1_3_2_7_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1021/cr950046o"
    },
    {
      "key": "e_1_3_2_8_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1007/s007750050018"
    },
    {
      "key": "e_1_3_2_9_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0021-9258(18)96527-0"
    },
    {
      "key": "e_1_3_2_10_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1007/978-1-4684-3270-1_43"
    },
    {
      "key": "e_1_3_2_11_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1146/annurev.nutr.22.012502.114457"
    },
    {
      "key": "e_1_3_2_12_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1196/annals.1306.024"
    },
    {
      "key": "e_1_3_2_13_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.271.5255.1552"
    },
    {
      "key": "e_1_3_2_14_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0065-3233(02)60055-5"
    },
    {
      "key": "e_1_3_2_15_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1046/j.1365-2958.2003.03368.x"
    },
    {
      "key": "e_1_3_2_16_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.270.3.1098"
    },
    {
      "key": "e_1_3_2_17_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0092-8674(94)90345-X"
    },
    {
      "key": "e_1_3_2_18_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0092-8674(94)90346-8"
    },
    {
      "key": "e_1_3_2_19_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0968-0004(98)01192-X"
    },
    {
      "key": "e_1_3_2_20_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1023/A:1020771000746"
    },
    {
      "key": "e_1_3_2_21_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.273.36.23274"
    },
    {
      "key": "e_1_3_2_22_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0014-5793(03)01218-3"
    },
    {
      "key": "e_1_3_2_23_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1007/s00775-003-0456-5"
    },
    {
      "key": "e_1_3_2_24_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.M307019200"
    },
    {
      "key": "e_1_3_2_25_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0076-6879(97)76068-3"
    },
    {
      "key": "e_1_3_2_26_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/nar/28.1.235"
    },
    {
      "key": "e_1_3_2_27_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.1925561"
    },
    {
      "key": "e_1_3_2_28_2",
      "first-page": "226",
      "year": "2001",
      "unstructured": "Otwinowski, Z. & Minor, W. (2001) in International Tables for Crystallography, eds. Rossman, M. & Arnold, E. (Kluwer, Dordrecht, The Netherlands), Vol. F, pp. 226-235.",
      "journal-title": "International Tables for Crystallography"
    },
    {
      "key": "e_1_3_2_29_2",
      "unstructured": "Evans P. (1993) in Proceedings of CCP4 Study Weekend on Data Collection and Processing eds. Sawyer L. Isaacs N. & Bailey S. (SERC Daresbury Laboratory Warrington U.K.) pp. 114-122."
    },
    {
      "key": "e_1_3_2_30_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0959-440X(99)00020-2"
    },
    {
      "key": "e_1_3_2_31_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0022-2836(68)90205-2"
    },
    {
      "key": "e_1_3_2_32_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1107/S0907444998003254"
    },
    {
      "key": "e_1_3_2_33_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1107/S0907444995008754"
    },
    {
      "key": "e_1_3_2_34_2",
      "first-page": "353",
      "year": "2001",
      "unstructured": "Kleywegt, G. J., Zou, J.-Y., Kjeldgaard, M. & Jones, T. A. (2001) in International Tables for Crystallography, eds. Rossman, M. & Arnold, E. (Kluwer, Dordrecht, The Netherlands), Vol. F, pp. 353-356, 366-368.",
      "journal-title": "International Tables for Crystallography"
    },
    {
      "key": "e_1_3_2_35_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/nsb0498-310"
    },
    {
      "key": "e_1_3_2_36_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0022-2836(92)90583-6"
    },
    {
      "key": "e_1_3_2_37_2",
      "first-page": "601",
      "volume": "9",
      "year": "2002",
      "unstructured": "Hakulinen, N., Kiiskinen, L. L., Kruus, K., Saloheimo, M., Paananen, A., Koivula, A. & Rouvinen, J. (2002) Nat. Struct. Biol. 9, 601-605.12118243",
      "journal-title": "Nat. Struct. Biol."
    },
    {
      "key": "e_1_3_2_38_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.M204571200"
    },
    {
      "key": "e_1_3_2_39_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.052710499"
    },
    {
      "key": "e_1_3_2_40_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/jmbi.1993.1489"
    },
    {
      "key": "e_1_3_2_41_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1107/S0108767386099622"
    },
    {
      "key": "e_1_3_2_42_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1107/S0907444996012255"
    },
    {
      "key": "e_1_3_2_43_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1107/S0907444900014736"
    },
    {
      "key": "e_1_3_2_44_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1107/S0108767390010224"
    },
    {
      "key": "e_1_3_2_45_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1107/S0907444904019158"
    },
    {
      "key": "e_1_3_2_46_2",
      "unstructured": "DeLano W. L. (2002) pymol (DeLano Scientific San Carlos CA)."
    },
    {
      "key": "e_1_3_2_47_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/jmbi.1993.1215"
    },
    {
      "key": "e_1_3_2_48_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1021/bi992334a"
    },
    {
      "key": "e_1_3_2_49_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1021/ja00255a032"
    },
    {
      "key": "e_1_3_2_50_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/1521-3773(20011217)40:24<4570::AID-ANIE4570>3.0.CO;2-4"
    },
    {
      "key": "e_1_3_2_51_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1021/ja003975s"
    },
    {
      "key": "e_1_3_2_52_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1021/bi011979j"
    },
    {
      "key": "e_1_3_2_53_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1007/s007750050156"
    },
    {
      "key": "e_1_3_2_54_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1021/ja049220t"
    },
    {
      "key": "e_1_3_2_55_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1021/bi0201318"
    },
    {
      "key": "e_1_3_2_56_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1128/JB.186.22.7815-7817.2004"
    },
    {
      "key": "e_1_3_2_57_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.M302963200"
    },
    {
      "key": "e_1_3_2_58_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1021/ja010365z"
    },
    {
      "key": "e_1_3_2_59_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1021/bi047379c"
    },
    {
      "key": "e_1_3_2_60_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.273.35.22415"
    },
    {
      "key": "e_1_3_2_61_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0014-5793(00)01435-6"
    },
    {
      "key": "e_1_3_2_62_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/yea.1237"
    },
    {
      "key": "e_1_3_2_63_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1021/ja00037a004"
    },
    {
      "key": "e_1_3_2_64_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1042/bj20031921"
    }
  ],
  "container-title": "Proceedings of the National Academy of Sciences",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://pnas.org/doi/pdf/10.1073/pnas.0506227102",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2022,
        4,
        12
      ]
    ],
    "date-time": "2022-04-12T18:04:18Z",
    "timestamp": 1649786658000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://pnas.org/doi/full/10.1073/pnas.0506227102"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        2005,
        10,
        17
      ]
    ]
  },
  "references-count": 64,
  "journal-issue": {
    "issue": "43",
    "published-print": {
      "date-parts": [
        [
          2005,
          10,
          25
        ]
      ]
    }
  },
  "alternative-id": [
    "10.1073/pnas.0506227102"
  ],
  "URL": "http://dx.doi.org/10.1073/pnas.0506227102",
  "relation": {},
  "ISSN": [
    "0027-8424",
    "1091-6490"
  ],
  "subject": [],
  "container-title-short": "Proc. Natl. Acad. Sci. U.S.A.",
  "published": {
    "date-parts": [
      [
        2005,
        10,
        17
      ]
    ]
  },
  "assertion": [
    {
      "value": "2005-07-21",
      "order": 0,
      "name": "received",
      "label": "Received",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    },
    {
      "value": "2005-09-08",
      "order": 1,
      "name": "accepted",
      "label": "Accepted",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    },
    {
      "value": "2005-10-17",
      "order": 2,
      "name": "published",
      "label": "Published",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    }
  ]
}