Wassenaar Tsjerk A, Quax Wim J, Mark Alan E
Groningen Biomolecular Sciences and Biotechnology Institute (GBB), Department of Biophysical Chemistry, University of Groningen, 9747AG Groningen, The Netherlands.
Proteins. 2008 Feb 1;70(2):333-43. doi: 10.1002/prot.21541.
The Death Receptor 5 (DR5), a member of tumor necrosis factor receptor (TNFR) superfamily of receptors, triggers apoptosis (programmed cell death) when stimulated by its tridentate ligand TRAIL. Until recently it was generally assumed that the activation of DR5 resulted from the recruitment of three independent receptor units, leading to the trimerization of intracellular domains. However, there is mounting evidence to suggest that, in the absence of ligand, such cytokine receptors primarily reside as preformed complexes. In this work, molecular dynamics simulations of the TRAIL-DR5 complex, the unbound receptor trimer and individual receptor monomers are compared to gain insight in the mechanism of activation. The results suggest that, in the absence of TRAIL, DR5 has a strong propensity to self-associate and that this is primarily mediated through interactions of the membrane proximal domains. The association of the free receptors leads to a loss of the threefold symmetry found within the receptor-ligand complex. The simulations suggest that the primary role of TRAIL is to induce threefold-symmetry within the DR5 complex and to constrain the receptor to a specific conformation. The implications of this in terms of the mechanism by which the receptor switches from an inactive to an active state are discussed.
死亡受体5（DR5）是肿瘤坏死因子受体（TNFR）超家族受体的成员之一，当受到其三齿配体TRAIL刺激时，会引发细胞凋亡（程序性细胞死亡）。直到最近，人们普遍认为DR5的激活是由于三个独立受体单元的募集，导致细胞内结构域三聚化。然而，越来越多的证据表明，在没有配体的情况下，这种细胞因子受体主要以预先形成的复合物形式存在。在这项工作中，对TRAIL-DR5复合物、未结合的受体三聚体和单个受体单体进行了分子动力学模拟，以深入了解激活机制。结果表明，在没有TRAIL的情况下，DR5具有很强的自我缔合倾向，这主要是通过膜近端结构域的相互作用介导的。游离受体的缔合导致受体-配体复合物中发现的三重对称性丧失。模拟结果表明，TRAIL的主要作用是在DR5复合物中诱导三重对称性，并将受体限制在特定构象。本文讨论了这在受体从无活性状态转变为活性状态的机制方面的意义。
