Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 288, Issue 44, Pages 31624-31634Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.491928
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Funding
- European Molecular Biology Organization long term fellowship [EMBO ALTF 102-2010]
- European Research Council [ERC281851_DYNACOM]
- European Molecular Biology Organization short term fellowship
- Biotechnology and Biological Sciences Research Council (Swindon, UK) [BB/H013024/1]
- Cancer Research UK [C303/A7399]
- Wellcome Trust [083524/Z/07/Z]
- BBSRC [BB/H013024/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/H013024/1] Funding Source: researchfish
- Cancer Research UK [14301] Funding Source: researchfish
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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 macromolecule 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 (similar to 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.
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