DOI: 10.1126/science.1176326. An E3 Ligase Possessing an Iron-Responsive Hemerythrin Domain Is a Regulator of Iron Homeostasis

An E3 Ligase Possessing an Iron-Responsive Hemerythrin Domain Is a Regulator of Iron Homeostasis

10.1126/science.1176326

Crossref journal-article

American Association for the Advancement of Science (AAAS)

Science (221)

Abstract

Iron Sensor Intracellular iron is an essential cofactor for many proteins, but can also damage macromolecules, so its levels are carefully controlled. Cellular iron homeostasis is mediated by iron regulatory proteins that regulate the expression of genes involved in iron uptake and storage. However, it is not clear how cells sense iron bioavailability (see the Perspective by Rouault ). Using different approaches, Salahudeen et al. (p. 722 , published online 17 September) and Vashisht et al. (p. 718 , published online 17 September) have identified the F-box protein FBXL5 as a human iron sensor. FBXL5 is part of an E3 ubiquitin ligase complex that regulates the degradation of iron regulatory proteins and thereby cellular iron levels. It contains a hemerythrin domain that binds iron and acts as an iron-dependent regulatory switch, causing the degradation of FBXL5 under low iron conditions. This alternative pathway for the regulation of iron homeostasis has implications for both normal cellular physiology and disease.

Bibliography

Salahudeen, A. A., Thompson, J. W., Ruiz, J. C., Ma, H.-W., Kinch, L. N., Li, Q., Grishin, N. V., & Bruick, R. K. (2009). An E3 Ligase Possessing an Iron-Responsive Hemerythrin Domain Is a Regulator of Iron Homeostasis. Science, 326(5953), 722â726.

Authors 8

Ameen A. Salahudeen (first)
Joel W. Thompson (additional)
Julio C. Ruiz (additional)
He-Wen Ma (additional)
Lisa N. Kinch (additional)
Qiming Li (additional)
Nick V. Grishin (additional)
Richard K. Bruick (additional)

References 26 Referenced 360

Dates

Type	When
Created	15 years, 11 months ago (Sept. 18, 2009, 1:28 a.m.)
Deposited	1 year, 7 months ago (Jan. 10, 2024, 3:29 a.m.)
Indexed	20 hours, 43 minutes ago (Aug. 31, 2025, 6:27 a.m.)
Issued	15 years, 10 months ago (Oct. 30, 2009)
Published	15 years, 10 months ago (Oct. 30, 2009)
Published Print	15 years, 10 months ago (Oct. 30, 2009)

Funders 0

None

BibTeX

@article{Salahudeen_2009, title={An E3 Ligase Possessing an Iron-Responsive Hemerythrin Domain Is a Regulator of Iron Homeostasis}, volume={326}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.1176326}, DOI={10.1126/science.1176326}, number={5953}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Salahudeen, Ameen A. and Thompson, Joel W. and Ruiz, Julio C. and Ma, He-Wen and Kinch, Lisa N. and Li, Qiming and Grishin, Nick V. and Bruick, Richard K.}, year={2009}, month=oct, pages={722–726} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        8,
        31
      ]
    ],
    "date-time": "2025-08-31T10:27:38Z",
    "timestamp": 1756636058682
  },
  "reference-count": 26,
  "publisher": "American Association for the Advancement of Science (AAAS)",
  "issue": "5953",
  "content-domain": {
    "domain": [],
    "crossmark-restriction": false
  },
  "published-print": {
    "date-parts": [
      [
        2009,
        10,
        30
      ]
    ]
  },
  "abstract": "<jats:title>Iron Sensor</jats:title>\n          <jats:p>\n            Intracellular iron is an essential cofactor for many proteins, but can also damage macromolecules, so its levels are carefully controlled. Cellular iron homeostasis is mediated by iron regulatory proteins that regulate the expression of genes involved in iron uptake and storage. However, it is not clear how cells sense iron bioavailability (see the Perspective by\n            <jats:bold>\n              <jats:related-article xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"doi\" issue=\"5953\" page=\"676\" related-article-type=\"in-this-issue\" vol=\"326\" xlink:href=\"10.1126/science.1181938\">Rouault</jats:related-article>\n            </jats:bold>\n            ). Using different approaches,\n            <jats:bold>\n              Salahudeen\n              <jats:italic>et al.</jats:italic>\n            </jats:bold>\n            (p.\n            <jats:related-article xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"doi\" page=\"722\" related-article-type=\"in-this-issue\" vol=\"326\" xlink:href=\"10.1126/science.1176326\">722</jats:related-article>\n            , published online 17 September) and\n            <jats:bold>\n              Vashisht\n              <jats:italic>et al.</jats:italic>\n            </jats:bold>\n            (p.\n            <jats:related-article xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"doi\" page=\"718\" related-article-type=\"in-this-issue\" vol=\"326\" xlink:href=\"10.1126/science.1176333\">718</jats:related-article>\n            , published online 17 September) have identified the F-box protein FBXL5 as a human iron sensor. FBXL5 is part of an E3 ubiquitin ligase complex that regulates the degradation of iron regulatory proteins and thereby cellular iron levels. It contains a hemerythrin domain that binds iron and acts as an iron-dependent regulatory switch, causing the degradation of FBXL5 under low iron conditions. This alternative pathway for the regulation of iron homeostasis has implications for both normal cellular physiology and disease.\n          </jats:p>",
  "DOI": "10.1126/science.1176326",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2009,
        9,
        18
      ]
    ],
    "date-time": "2009-09-18T05:28:42Z",
    "timestamp": 1253251722000
  },
  "page": "722-726",
  "source": "Crossref",
  "is-referenced-by-count": 360,
  "title": "An E3 Ligase Possessing an Iron-Responsive Hemerythrin Domain Is a Regulator of Iron Homeostasis",
  "prefix": "10.1126",
  "volume": "326",
  "author": [
    {
      "given": "Ameen A.",
      "family": "Salahudeen",
      "sequence": "first",
      "affiliation": [
        {
          "name": "Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."
        }
      ]
    },
    {
      "given": "Joel W.",
      "family": "Thompson",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."
        }
      ]
    },
    {
      "given": "Julio C.",
      "family": "Ruiz",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."
        }
      ]
    },
    {
      "given": "He-Wen",
      "family": "Ma",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."
        }
      ]
    },
    {
      "given": "Lisa N.",
      "family": "Kinch",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."
        }
      ]
    },
    {
      "given": "Qiming",
      "family": "Li",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."
        }
      ]
    },
    {
      "given": "Nick V.",
      "family": "Grishin",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."
        }
      ]
    },
    {
      "given": "Richard K.",
      "family": "Bruick",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."
        }
      ]
    }
  ],
  "member": "221",
  "reference": [
    {
      "key": "e_1_3_2_2_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1146/annurev.nutr.28.061807.155521"
    },
    {
      "key": "e_1_3_2_3_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.bbamcr.2006.05.004"
    },
    {
      "key": "e_1_3_2_4_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1146/annurev.med.57.121304.131310"
    },
    {
      "key": "e_1_3_2_5_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0070-2153(07)00006-3"
    },
    {
      "key": "e_1_3_2_6_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0092-8674(04)00343-5"
    },
    {
      "key": "e_1_3_2_7_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/nchembio807"
    },
    {
      "key": "e_1_3_2_8_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.86.10.3574"
    },
    {
      "key": "e_1_3_2_9_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.270.37.21645"
    },
    {
      "key": "e_1_3_2_10_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0021-9258(18)47367-X"
    },
    {
      "key": "e_1_3_2_11_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.95.9.4924"
    },
    {
      "key": "e_1_3_2_12_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/ncb952"
    },
    {
      "key": "e_1_3_2_13_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S1079-9796(03)00161-X"
    },
    {
      "key": "e_1_3_2_14_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.M302798200"
    },
    {
      "key": "e_1_3_2_15_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1128/MCB.24.3.954-965.2004"
    },
    {
      "key": "e_1_3_2_16_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.bbamcr.2007.07.010"
    },
    {
      "key": "e_1_3_2_18_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.bbrc.2007.05.068"
    },
    {
      "key": "e_1_3_2_19_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.bbamcr.2004.09.027"
    },
    {
      "key": "e_1_3_2_20_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/j.1460-2075.1995.tb00219.x"
    },
    {
      "key": "e_1_3_2_21_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/sj.emboj.7600954"
    },
    {
      "key": "e_1_3_2_22_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1128/MCB.23.19.6973-6981.2003"
    },
    {
      "key": "e_1_3_2_23_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1021/cr00027a008"
    },
    {
      "key": "e_1_3_2_24_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1111/j.1574-6968.2007.01011.x"
    },
    {
      "key": "e_1_3_2_25_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1021/bi00216a037"
    },
    {
      "key": "e_1_3_2_26_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/nprot.2006.202"
    },
    {
      "key": "e_1_3_2_27_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.96.16.9124"
    },
    {
      "key": "e_1_3_2_28_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.tplants.2009.01.003"
    }
  ],
  "container-title": "Science",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://www.science.org/doi/pdf/10.1126/science.1176326",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2024,
        1,
        10
      ]
    ],
    "date-time": "2024-01-10T08:29:16Z",
    "timestamp": 1704875356000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://www.science.org/doi/10.1126/science.1176326"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        2009,
        10,
        30
      ]
    ]
  },
  "references-count": 26,
  "journal-issue": {
    "issue": "5953",
    "published-print": {
      "date-parts": [
        [
          2009,
          10,
          30
        ]
      ]
    }
  },
  "alternative-id": [
    "10.1126/science.1176326"
  ],
  "URL": "http://dx.doi.org/10.1126/science.1176326",
  "relation": {
    "has-review": [
      {
        "id-type": "doi",
        "id": "10.3410/f.1570988.9214057",
        "asserted-by": "object"
      },
      {
        "id-type": "doi",
        "id": "10.3410/f.1570988.1061090",
        "asserted-by": "object"
      }
    ]
  },
  "ISSN": [
    "0036-8075",
    "1095-9203"
  ],
  "subject": [],
  "container-title-short": "Science",
  "published": {
    "date-parts": [
      [
        2009,
        10,
        30
      ]
    ]
  }
}