DOI: 10.1073/pnas.1004148107. Architecture of Eph receptor clusters

10.1073/pnas.1004148107

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Eph receptor tyrosine kinases and their ephrin ligands regulate cell navigation during normal and oncogenic development. Signaling of Ephs is initiated in a multistep process leading to the assembly of higher-order signaling clusters that set off bidirectional signaling in interacting cells. However, the structural and mechanistic details of this assembly remained undefined. Here we present high-resolution structures of the complete EphA2 ectodomain and complexes with ephrin-A1 and A5 as the base unit of an Eph cluster. The structures reveal an elongated architecture with novel Eph/Eph interactions, both within and outside of the Eph ligand-binding domain, that suggest the molecular mechanism underlying Eph/ephrin clustering. Structure-function analysis, by using site-directed mutagenesis and cell-based signaling assays, confirms the importance of the identified oligomerization interfaces for Eph clustering.

Bibliography

Himanen, J. P., Yermekbayeva, L., Janes, P. W., Walker, J. R., Xu, K., Atapattu, L., Rajashankar, K. R., Mensinga, A., Lackmann, M., Nikolov, D. B., & Dhe-Paganon, S. (2010). Architecture of Eph receptor clusters. Proceedings of the National Academy of Sciences, 107(24), 10860â10865.

Authors 11

Juha P. Himanen (first)
Laila Yermekbayeva (additional)
Peter W. Janes (additional)
John R. Walker (additional)
Kai Xu (additional)
Lakmali Atapattu (additional)
Kanagalaghatta R. Rajashankar (additional)
Anneloes Mensinga (additional)
Martin Lackmann (additional)
Dimitar B. Nikolov (additional)
Sirano Dhe-Paganon (additional)

References 23 Referenced 230

Dates

Type	When
Created	15 years, 3 months ago (May 26, 2010, 11:15 p.m.)
Deposited	3 years, 4 months ago (April 12, 2022, 6:43 p.m.)
Indexed	1 day, 13 hours ago (Sept. 3, 2025, 7:09 a.m.)
Issued	15 years, 3 months ago (May 26, 2010)
Published	15 years, 3 months ago (May 26, 2010)
Published Online	15 years, 3 months ago (May 26, 2010)
Published Print	15 years, 2 months ago (June 15, 2010)

Funders 0

None

BibTeX

@article{Himanen_2010, title={Architecture of Eph receptor clusters}, volume={107}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.1004148107}, DOI={10.1073/pnas.1004148107}, number={24}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Himanen, Juha P. and Yermekbayeva, Laila and Janes, Peter W. and Walker, John R. and Xu, Kai and Atapattu, Lakmali and Rajashankar, Kanagalaghatta R. and Mensinga, Anneloes and Lackmann, Martin and Nikolov, Dimitar B. and Dhe-Paganon, Sirano}, year={2010}, month=may, pages={10860–10865} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        9,
        3
      ]
    ],
    "date-time": "2025-09-03T11:09:30Z",
    "timestamp": 1756897770314
  },
  "reference-count": 23,
  "publisher": "Proceedings of the National Academy of Sciences",
  "issue": "24",
  "content-domain": {
    "domain": [
      "www.pnas.org"
    ],
    "crossmark-restriction": true
  },
  "published-print": {
    "date-parts": [
      [
        2010,
        6,
        15
      ]
    ]
  },
  "abstract": "<jats:p>Eph receptor tyrosine kinases and their ephrin ligands regulate cell navigation during normal and oncogenic development. Signaling of Ephs is initiated in a multistep process leading to the assembly of higher-order signaling clusters that set off bidirectional signaling in interacting cells. However, the structural and mechanistic details of this assembly remained undefined. Here we present high-resolution structures of the complete EphA2 ectodomain and complexes with ephrin-A1 and A5 as the base unit of an Eph cluster. The structures reveal an elongated architecture with novel Eph/Eph interactions, both within and outside of the Eph ligand-binding domain, that suggest the molecular mechanism underlying Eph/ephrin clustering. Structure-function analysis, by using site-directed mutagenesis and cell-based signaling assays, confirms the importance of the identified oligomerization interfaces for Eph clustering.</jats:p>",
  "DOI": "10.1073/pnas.1004148107",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2010,
        5,
        27
      ]
    ],
    "date-time": "2010-05-27T03:15:52Z",
    "timestamp": 1274930152000
  },
  "page": "10860-10865",
  "update-policy": "http://dx.doi.org/10.1073/pnas.cm10313",
  "source": "Crossref",
  "is-referenced-by-count": 230,
  "title": "Architecture of Eph receptor clusters",
  "prefix": "10.1073",
  "volume": "107",
  "author": [
    {
      "given": "Juha P.",
      "family": "Himanen",
      "sequence": "first",
      "affiliation": [
        {
          "name": "Structural Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065;"
        }
      ]
    },
    {
      "given": "Laila",
      "family": "Yermekbayeva",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada;"
        }
      ]
    },
    {
      "given": "Peter W.",
      "family": "Janes",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia;"
        }
      ]
    },
    {
      "given": "John R.",
      "family": "Walker",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada;"
        }
      ]
    },
    {
      "given": "Kai",
      "family": "Xu",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Structural Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065;"
        }
      ]
    },
    {
      "given": "Lakmali",
      "family": "Atapattu",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia;"
        }
      ]
    },
    {
      "given": "Kanagalaghatta R.",
      "family": "Rajashankar",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Advanced Photon Source, Argonne National Laboratory, 9700 S. Cass Avenue, Argonne, IL 60439; and"
        }
      ]
    },
    {
      "given": "Anneloes",
      "family": "Mensinga",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia;"
        }
      ]
    },
    {
      "given": "Martin",
      "family": "Lackmann",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia;"
        }
      ]
    },
    {
      "given": "Dimitar B.",
      "family": "Nikolov",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Structural Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065;"
        }
      ]
    },
    {
      "given": "Sirano",
      "family": "Dhe-Paganon",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada;"
        },
        {
          "name": "Department of Physiology, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada"
        }
      ]
    }
  ],
  "member": "341",
  "published-online": {
    "date-parts": [
      [
        2010,
        5,
        26
      ]
    ]
  },
  "reference": [
    {
      "key": "e_1_3_4_1_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0166-2236(02)00005-X"
    },
    {
      "key": "e_1_3_4_2_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/nrm1662"
    },
    {
      "key": "e_1_3_4_3_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.273.32.20228"
    },
    {
      "key": "e_1_3_4_4_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.ceb.2007.08.004"
    },
    {
      "key": "e_1_3_4_5_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1083/jcb.200312001"
    },
    {
      "key": "e_1_3_4_6_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.M309326200"
    },
    {
      "key": "e_1_3_4_7_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/nn1655"
    },
    {
      "key": "e_1_3_4_8_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.1181729"
    },
    {
      "key": "e_1_3_4_9_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/embor.2009.91"
    },
    {
      "key": "e_1_3_4_10_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/414933a"
    },
    {
      "key": "e_1_3_4_11_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1158/0008-5472.CAN-05-0758"
    },
    {
      "key": "e_1_3_4_12_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/stke.115re2"
    },
    {
      "key": "e_1_3_4_13_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/ncb823"
    },
    {
      "key": "e_1_3_4_14_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0076-6879(97)76066-X"
    },
    {
      "key": "e_1_3_4_15_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1107/S0021889807021206"
    },
    {
      "key": "e_1_3_4_16_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1107/S0907444904019158"
    },
    {
      "key": "e_1_3_4_17_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1107/S0907444996012255"
    },
    {
      "key": "e_1_3_4_18_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1107/S0907444998003254"
    },
    {
      "key": "e_1_3_4_19_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1107/S0907444994003112"
    },
    {
      "key": "e_1_3_4_20_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1107/S0021889805038987"
    },
    {
      "key": "e_1_3_4_21_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/nar/gkh398"
    },
    {
      "key": "e_1_3_4_22_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1083/jcb.200304018"
    },
    {
      "key": "e_1_3_4_23_2",
      "doi-asserted-by": "crossref",
      "unstructured": "E Seiradake K Harlos G Sutton AR Aricescu EY Jones An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly. Nat Struct Mol Biol 17 398\u2013402 PMID: 20228801. (2010).",
      "DOI": "10.1038/nsmb.1782"
    }
  ],
  "container-title": "Proceedings of the National Academy of Sciences",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://pnas.org/doi/pdf/10.1073/pnas.1004148107",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2022,
        4,
        12
      ]
    ],
    "date-time": "2022-04-12T22:43:18Z",
    "timestamp": 1649803398000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://pnas.org/doi/full/10.1073/pnas.1004148107"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        2010,
        5,
        26
      ]
    ]
  },
  "references-count": 23,
  "journal-issue": {
    "issue": "24",
    "published-print": {
      "date-parts": [
        [
          2010,
          6,
          15
        ]
      ]
    }
  },
  "alternative-id": [
    "10.1073/pnas.1004148107"
  ],
  "URL": "http://dx.doi.org/10.1073/pnas.1004148107",
  "relation": {
    "has-review": [
      {
        "id-type": "doi",
        "id": "10.3410/f.723910301.793515743",
        "asserted-by": "object"
      }
    ]
  },
  "ISSN": [
    "0027-8424",
    "1091-6490"
  ],
  "subject": [],
  "container-title-short": "Proc. Natl. Acad. Sci. U.S.A.",
  "published": {
    "date-parts": [
      [
        2010,
        5,
        26
      ]
    ]
  },
  "assertion": [
    {
      "value": "2010-05-26",
      "order": 2,
      "name": "published",
      "label": "Published",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    }
  ]
}