Orth Barbara, Sander Bodo, Möglich Andreas, Diederichs Kay, Eilers Martin, Lorenz Sonja
Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, 97080 Würzburg, Germany; Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, 97080 Würzburg, Germany.
Structure. 2021 Nov 4;29(11):1230-1240.e5. doi: 10.1016/j.str.2021.06.005. Epub 2021 Jun 28.
The repurposing of structurally conserved protein domains in different functional contexts is thought to be a driving force in the evolution of complex protein interaction networks. The BTB/POZ domain is such a versatile binding module that occurs over 200 times in the human proteome with diverse protein-specific adaptations. In BTB-zinc-finger transcription factors, the BTB domain drives homo- and heterodimerization as well as interactions with non-BTB-domain-containing proteins. Which mechanisms encode specificity in these interactions at a structural level is incompletely understood. Here, we uncover an atypical peptide-binding site in the BTB domain of the MYC-interacting zinc-finger protein 1 (MIZ1) that arises from local flexibility of the core BTB fold and may provide a target site for MIZ1-directed therapeutic approaches. Intriguingly, the identified binding mode requires the BTB domain to be in a homodimeric state, thus holding opportunities for functional discrimination between homo- and heterodimers of MIZ1 in the cell.
在不同功能背景下对结构保守的蛋白质结构域进行重新利用被认为是复杂蛋白质相互作用网络进化的驱动力。BTB/POZ结构域就是这样一个多功能的结合模块，在人类蛋白质组中出现超过200次，具有多种蛋白质特异性适应性变化。在BTB-锌指转录因子中，BTB结构域驱动同二聚化和异二聚化，以及与不含BTB结构域的蛋白质相互作用。在结构水平上，哪些机制编码了这些相互作用中的特异性，目前还不完全清楚。在这里，我们在与MYC相互作用的锌指蛋白1（MIZ1）的BTB结构域中发现了一个非典型的肽结合位点，它源于核心BTB折叠的局部灵活性，可能为针对MIZ1的治疗方法提供靶点。有趣的是，所确定的结合模式要求BTB结构域处于同二聚体状态，从而为区分细胞中MIZ1的同二聚体和异二聚体的功能提供了机会。
