Turning the RING domain protein MdmX into an active ubiquitin-protein ligase

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2010
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Iyappan, Saravanakumar
Wollscheid, Hans-Peter
Rojas-Fernandez, Alejandro
Tang, Hao-Chen
Singh, Rajesh Kumar
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The journal of biological chemistry. 2010, 285(43), pp. 33065-33072. ISSN 0021-9258. eISSN 1083-351X. Available under: doi: 10.1074/jbc.M110.115113
Zusammenfassung

The related RING domain proteins MdmX and Mdm2 are best known for their role as negative regulators of the tumor suppressor p53. However, although Mdm2 functions as a ubiquitin ligase for p53, MdmX does not have appreciable ubiquitin ligase activity. In this study, we performed a mutational analysis of the RING domain of MdmX, and we identified two distinct regions that, when replaced by the respective regions of Mdm2, turn MdmX into an active ubiquitin ligase for p53. Mdm2 and MdmX form homodimers as well as heterodimers with each other. One of the regions identified localizes to the dimer interface indicating that subtle conformational changes in this region either affect dimer stability and/or the interaction with the ubiquitin-conjugating enzyme UbcH5b. The second region contains the cryptic nucleolar localization signal of Mdm2 but is also assumed to be involved in the interaction with UbcH5b. Here, we show that this region has a significant impact on the ability of respective MdmX mutants to functionally interact with UbcH5b in vitro supporting the notion that this region serves two distinct functional purposes, nucleolar localization and ubiquitin ligase activity. Finally, evidence is provided to suggest that the RING domain of Mdm2 not only binds to UbcH5b but also acts as an allosteric activator of UbcH5b.

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570 Biowissenschaften, Biologie
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Ubiquitin, p53
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ISO 690IYAPPAN, Saravanakumar, Hans-Peter WOLLSCHEID, Alejandro ROJAS-FERNANDEZ, Andreas MARQUARDT, Hao-Chen TANG, Rajesh Kumar SINGH, Martin SCHEFFNER, 2010. Turning the RING domain protein MdmX into an active ubiquitin-protein ligase. In: The journal of biological chemistry. 2010, 285(43), pp. 33065-33072. ISSN 0021-9258. eISSN 1083-351X. Available under: doi: 10.1074/jbc.M110.115113
BibTex
@article{Iyappan2010Turni-7669,
  year={2010},
  doi={10.1074/jbc.M110.115113},
  title={Turning the RING domain protein MdmX into an active ubiquitin-protein ligase},
  number={43},
  volume={285},
  issn={0021-9258},
  journal={The journal of biological chemistry},
  pages={33065--33072},
  author={Iyappan, Saravanakumar and Wollscheid, Hans-Peter and Rojas-Fernandez, Alejandro and Marquardt, Andreas and Tang, Hao-Chen and Singh, Rajesh Kumar and Scheffner, Martin}
}
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