REPIN, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Cell Commun Signal. 2021 Jan 6;19(1):2. doi: 10.1186/s12964-020-00686-8.
Signal fidelity depends on protein-protein interaction-'hubs' integrating cues from large interactomes. Recently, and based on a common secondary structure motif, the αα-hubs were defined, which are small α-helical domains of large, modular proteins binding intrinsically disordered transcriptional regulators.
Comparative structural biology.
We assign the harmonin-homology-domain (HHD, also named the harmonin N-terminal domain, NTD) present in large proteins such as harmonin, whirlin, cerebral cavernous malformation 2, and regulator of telomere elongation 1 to the αα-hubs. The new member of the αα-hubs expands functionality to include scaffolding of supra-modular complexes mediating sensory perception, neurovascular integrity and telomere regulation, and reveal novel features of the αα-hubs. As a common trait, the αα-hubs bind intrinsically disordered ligands of similar properties integrating similar cellular cues, but without cross-talk.
The inclusion of the HHD in the αα-hubs has uncovered new features, exemplifying the utility of identifying groups of hub domains, whereby discoveries in one member may cross-fertilize discoveries in others. These features make the αα-hubs unique models for decomposing signal specificity and fidelity. Using these as models, together with other suitable hub domain, we may advance the functional understanding of hub proteins and their role in cellular communication and signaling, as well as the role of intrinsically disordered proteins in signaling networks. Video Abstract.
信号保真度取决于蛋白质-蛋白质相互作用的“枢纽”，这些枢纽整合了来自大相互作用组的线索。最近，基于一个常见的二级结构模体，定义了 αα-枢纽，它们是结合内在无序转录调节剂的大型模块化蛋白质的小α-螺旋结构域。
比较结构生物学。
我们将大蛋白中存在的 harmonin 同源结构域（HHD，也称为 harmonin N 端结构域，NTD）分配给 αα-枢纽，这些大蛋白包括 harmonin、whirlin、脑动静脉畸形 2 和端粒延长调节因子 1。αα-枢纽的新成员扩展了其功能，包括介导感觉感知、神经血管完整性和端粒调节的超模块化复合物的支架，揭示了 αα-枢纽的新特征。作为一个共同的特征，αα-枢纽结合具有相似性质的内在无序配体，整合相似的细胞线索，但没有串扰。
将 HHD 纳入 αα-枢纽揭示了新的特征，证明了识别枢纽结构域组的实用性，其中一个成员的发现可能会促进其他成员的发现。这些特征使 αα-枢纽成为分解信号特异性和保真度的独特模型。使用这些模型以及其他合适的枢纽结构域，我们可以深入了解枢纽蛋白及其在细胞通讯和信号转导中的作用，以及内在无序蛋白在信号网络中的作用。视频摘要。
