Sigalov Alexander B
Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Mol Biosyst. 2010 Mar;6(3):451-61. doi: 10.1039/b916030m. Epub 2009 Nov 3.
Receptor-mediated signaling plays an important role in health and disease. Recent reports have revealed that many proteins that do not adopt globular structures under native conditions, thus termed intrinsically disordered, are involved in cell signaling. Intriguingly, physiologically relevant oligomerization of intrinsically disordered proteins has been recently observed and shown to exhibit unique biophysical characteristics. On the other hand, ligand-induced or -tuned receptor oligomerization is known to be a general feature of various cell surface receptors and to play a crucial role in signal transduction. In this work, I summarize several distinct features of protein disorder that are especially important as related to signal transduction. Further, I suggest signaling-related functional connections between intrinsic disorder, receptor and protein oligomericity and hypothesize that receptor oligomerization induced or tuned upon ligand binding outside the cell is translated across the membrane into protein oligomerization inside the cell, thus providing a general platform for receptor-mediated signaling. This structures our current multidisciplinary knowledge and views of the mechanisms governing the coupling of recognition to signal transduction and cell response. Importantly, this approach not only reveals previously unrecognized striking similarities in the basic mechanistic principles of function of numerous functionally diverse and unrelated surface membrane receptors, but also suggests the similarity between therapeutic targets, thus opening new horizons for both fundamental and clinically relevant studies.
受体介导的信号传导在健康和疾病中起着重要作用。最近的报道表明，许多在天然条件下不具有球状结构（因此被称为内在无序）的蛋白质参与了细胞信号传导。有趣的是，最近观察到内在无序蛋白质的生理相关寡聚化，并显示出独特的生物物理特性。另一方面，配体诱导或调节的受体寡聚化是各种细胞表面受体的普遍特征，并在信号转导中起关键作用。在这项工作中，我总结了蛋白质无序的几个独特特征，这些特征与信号转导相关时尤为重要。此外，我提出了内在无序、受体和蛋白质寡聚性之间与信号传导相关的功能联系，并假设细胞外配体结合诱导或调节的受体寡聚化通过膜转化为细胞内的蛋白质寡聚化，从而为受体介导的信号传导提供一个通用平台。这构建了我们目前关于控制识别与信号转导及细胞反应耦合机制的多学科知识和观点。重要的是，这种方法不仅揭示了众多功能多样且不相关的表面膜受体在基本功能机制原理上以前未被认识到的显著相似性，还暗示了治疗靶点之间的相似性，从而为基础研究和临床相关研究开辟了新的视野。
