Death Receptor 5 Networks Require Membrane Cholesterol for Proper Structure and Function.
Death Receptor 5 Networks Require Membrane Cholesterol for Proper Structure and Function.
复制标题
死亡受体 5 网络需要膜胆固醇才能实现适当的结构和功能。
DOI：
10.1016/j.jmb.2016.10.001
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发表时间：
2016
影响因子：
5.6
通讯作者：
Sachs,JonathanN
中科院分区：
文献类型：
--
作者：
Lewis,AndrewK;Valley,ChristopherC;Peery,StephenL;Brummel,Benjamin;Braun,AnthonyR;Karim,ChristineB;Sachs,JonathanN
死亡受体5（DR 5）是肿瘤坏死因子受体超家族的一个凋亡诱导成员，其活性与膜胆固醇含量有关。在配体结合后，DR 5在质膜内形成大簇，这通常被认为是受体在富含胆固醇的膜结构域中共定位的表现。然而，我们最近发现DR 5簇不仅仅是随机聚集的受体。相反，这些是由受体二聚体连接在一起的高度结构化的网络。这些二聚体通过特异性跨膜螺旋-螺旋相互作用稳定，包括受体长同种型中的二硫键。DR 5网络形成、跨膜螺旋二聚化、膜胆固醇和受体活性之间的复杂关系尚未建立。目前尚不清楚膜本身是否在驱动DR 5跨膜螺旋相互作用或网络形成中发挥积极作用。我们发现，细胞中胆固醇的消耗不会抑制DR 5网络的形成。然而，在胆固醇耗尽的细胞中形成的网络不能诱导半胱天冬酶切割。这些结果表明，活跃和不活跃的网络之间存在潜在的结构差异。作为证据，我们表明，胆固醇是必要的DR 5跨膜结构域的共价二聚化。分子模拟和实验在合成囊泡上的DR 5跨膜二聚体表明，二聚化是促进螺旋增加在一个较厚的双层。
Death receptor 5 (DR5) is an apoptosis-inducing member of the tumor necrosis factor receptor superfamily, whose activity has been linked to membrane cholesterol content. Upon ligand binding, DR5 forms large clusters within the plasma membrane that have often been assumed to be manifestations of receptor co-localization in cholesterol-rich membrane domains. However, we have recently shown that DR5 clusters are more than just randomly aggregated receptors. Instead, these are highly structured networks held together by receptor dimers. These dimers are stabilized by specific transmembrane helix–helix interactions, including a disulfide bond in the long isoform of the receptor. The complex relationships among DR5 network formation, transmembrane helix dimerization, membrane cholesterol, and receptor activity has not been established. It is unknown whether the membrane itself plays an active role in driving DR5 transmembrane helix interactions or in the formation of the networks. We show that cholesterol depletion in cells does not inhibit the formation of DR5 networks. However, the networks that form in cholesterol-depleted cells fail to induce caspase cleavage. These results suggest a potential structural difference between active and inactive networks. As evidence, we show that cholesterol is necessary for the covalent dimerization of DR5 transmembrane domains. Molecular simulations and experiments in synthetic vesicles on the DR5 transmembrane dimer suggest that dimerization is facilitated by increased helicity in a thicker bilayer.