The Geminin and Idas coiled coils preferentially form a heterodimer that inhibits Geminin function in DNA replication licensing

Christophe Caillat, Dafni-Eleftheria Pefani, Peter J. Gillespie, Stavros Taraviras, J. Julian Blow, Zoi Lygerou, Anastassis Perrakis

    Research output: Contribution to journalArticle

    10 Citations (Scopus)

    Abstract

    Geminin is an important regulator of proliferation and differentiation in metazoans, which predominantly inhibits the DNA replication licensing factor Cdt1, preventing genome over-replication. We show that Geminin preferentially forms stable coiled-coil heterodimers with its homologue, Idas. In contrast to Idas-Geminin heterodimers, Idas homodimers are thermodynamically unstable and are unlikely to exist as a stable macro-molecule under physiological conditions. The crystal structure of the homology regions of Idas in complex with Geminin showed a tight head-to-head heterodimeric coiled-coil. This Idas-Geminin heterodimer binds Cdt1 less strongly than Geminin-Geminin, still with high affinity (~30 nM), but with notably different thermodynamic properties. Consistently, in Xenopus egg extracts, Idas-Geminin is less active in licensing inhibition compared with a Geminin-Geminin homodimer. In human cultured cells, ectopic expression of Idas leads to limited over-replication, which is counteracted by Geminin co-expression. The properties of the Idas-Geminin complex suggest it as the functional form of Idas and provide a possible mechanism to modulate Geminin activity.
    Original languageEnglish
    Pages (from-to)31624-31634
    Number of pages11
    JournalJournal of Biological Chemistry
    Volume288
    Issue number44
    DOIs
    Publication statusPublished - Nov 2013

    Fingerprint

    Geminin
    Licensure
    DNA Replication
    DNA

    Cite this

    Caillat, Christophe ; Pefani, Dafni-Eleftheria ; Gillespie, Peter J. ; Taraviras, Stavros ; Blow, J. Julian ; Lygerou, Zoi ; Perrakis, Anastassis. / The Geminin and Idas coiled coils preferentially form a heterodimer that inhibits Geminin function in DNA replication licensing. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 44. pp. 31624-31634.
    @article{303e4c0aad4f493084b000c7ef8b4a05,
    title = "The Geminin and Idas coiled coils preferentially form a heterodimer that inhibits Geminin function in DNA replication licensing",
    abstract = "Geminin is an important regulator of proliferation and differentiation in metazoans, which predominantly inhibits the DNA replication licensing factor Cdt1, preventing genome over-replication. We show that Geminin preferentially forms stable coiled-coil heterodimers with its homologue, Idas. In contrast to Idas-Geminin heterodimers, Idas homodimers are thermodynamically unstable and are unlikely to exist as a stable macro-molecule under physiological conditions. The crystal structure of the homology regions of Idas in complex with Geminin showed a tight head-to-head heterodimeric coiled-coil. This Idas-Geminin heterodimer binds Cdt1 less strongly than Geminin-Geminin, still with high affinity (~30 nM), but with notably different thermodynamic properties. Consistently, in Xenopus egg extracts, Idas-Geminin is less active in licensing inhibition compared with a Geminin-Geminin homodimer. In human cultured cells, ectopic expression of Idas leads to limited over-replication, which is counteracted by Geminin co-expression. The properties of the Idas-Geminin complex suggest it as the functional form of Idas and provide a possible mechanism to modulate Geminin activity.",
    author = "Christophe Caillat and Dafni-Eleftheria Pefani and Gillespie, {Peter J.} and Stavros Taraviras and Blow, {J. Julian} and Zoi Lygerou and Anastassis Perrakis",
    year = "2013",
    month = "11",
    doi = "10.1074/jbc.M113.491928",
    language = "English",
    volume = "288",
    pages = "31624--31634",
    journal = "Journal of Biological Chemistry",
    issn = "0021-9258",
    publisher = "American Society for Biochemistry and Molecular Biology",
    number = "44",

    }

    The Geminin and Idas coiled coils preferentially form a heterodimer that inhibits Geminin function in DNA replication licensing. / Caillat, Christophe; Pefani, Dafni-Eleftheria; Gillespie, Peter J.; Taraviras, Stavros; Blow, J. Julian; Lygerou, Zoi; Perrakis, Anastassis.

    In: Journal of Biological Chemistry, Vol. 288, No. 44, 11.2013, p. 31624-31634.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - The Geminin and Idas coiled coils preferentially form a heterodimer that inhibits Geminin function in DNA replication licensing

    AU - Caillat, Christophe

    AU - Pefani, Dafni-Eleftheria

    AU - Gillespie, Peter J.

    AU - Taraviras, Stavros

    AU - Blow, J. Julian

    AU - Lygerou, Zoi

    AU - Perrakis, Anastassis

    PY - 2013/11

    Y1 - 2013/11

    N2 - Geminin is an important regulator of proliferation and differentiation in metazoans, which predominantly inhibits the DNA replication licensing factor Cdt1, preventing genome over-replication. We show that Geminin preferentially forms stable coiled-coil heterodimers with its homologue, Idas. In contrast to Idas-Geminin heterodimers, Idas homodimers are thermodynamically unstable and are unlikely to exist as a stable macro-molecule under physiological conditions. The crystal structure of the homology regions of Idas in complex with Geminin showed a tight head-to-head heterodimeric coiled-coil. This Idas-Geminin heterodimer binds Cdt1 less strongly than Geminin-Geminin, still with high affinity (~30 nM), but with notably different thermodynamic properties. Consistently, in Xenopus egg extracts, Idas-Geminin is less active in licensing inhibition compared with a Geminin-Geminin homodimer. In human cultured cells, ectopic expression of Idas leads to limited over-replication, which is counteracted by Geminin co-expression. The properties of the Idas-Geminin complex suggest it as the functional form of Idas and provide a possible mechanism to modulate Geminin activity.

    AB - Geminin is an important regulator of proliferation and differentiation in metazoans, which predominantly inhibits the DNA replication licensing factor Cdt1, preventing genome over-replication. We show that Geminin preferentially forms stable coiled-coil heterodimers with its homologue, Idas. In contrast to Idas-Geminin heterodimers, Idas homodimers are thermodynamically unstable and are unlikely to exist as a stable macro-molecule under physiological conditions. The crystal structure of the homology regions of Idas in complex with Geminin showed a tight head-to-head heterodimeric coiled-coil. This Idas-Geminin heterodimer binds Cdt1 less strongly than Geminin-Geminin, still with high affinity (~30 nM), but with notably different thermodynamic properties. Consistently, in Xenopus egg extracts, Idas-Geminin is less active in licensing inhibition compared with a Geminin-Geminin homodimer. In human cultured cells, ectopic expression of Idas leads to limited over-replication, which is counteracted by Geminin co-expression. The properties of the Idas-Geminin complex suggest it as the functional form of Idas and provide a possible mechanism to modulate Geminin activity.

    UR - http://www.scopus.com/inward/record.url?scp=84887078942&partnerID=8YFLogxK

    U2 - 10.1074/jbc.M113.491928

    DO - 10.1074/jbc.M113.491928

    M3 - Article

    VL - 288

    SP - 31624

    EP - 31634

    JO - Journal of Biological Chemistry

    JF - Journal of Biological Chemistry

    SN - 0021-9258

    IS - 44

    ER -