CRYSTALLOGRAPHIC EVIDENCE FOR DIMERIZATION OF UNLIGANDED TUMOR-NECROSIS-FACTOR RECEPTOR
CRYSTALLOGRAPHIC EVIDENCE FOR DIMERIZATION OF UNLIGANDED TUMOR-NECROSIS-FACTOR RECEPTOR
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DOI：
10.1074/jbc.270.22.13303
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发表时间：
1995-06-02
影响因子：
4.8
通讯作者：
SPRANG, SR
中科院分区：
文献类型：
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作者：
NAISMITH, JH;DEVINE, TQ;SPRANG, SR
肿瘤坏死因子（TNF）的细胞表面受体的活化受细胞质结构域的聚集影响，当两种或三种受体的细胞外结构域结合三聚体TNF α或TNF β时发生细胞质结构域的聚集。I型TNF受体胞外域（sTNF-R1）的结构，在TNF的情况下结晶，现在已经确定在2.25埃分辨率。受体本身是一个细长的分子，包括四个富含二硫键的结构域，几乎呈线性排列。与预期相反，unliganded域被发现关联成两种不同类型的二聚体，其中单体由局部双重对称轴相关。在一种情况下，受体彼此反平行，并通过与TNF结合位点重叠的界面缔合。如果完整的受体能够这样的关联，它们的胞质结构域将被分开超过100埃。这种相互作用可以在TNF不存在的情况下抑制信号传导。还观察到平行二聚体，其中二聚体界面与TNF结合位点良好分离。TNF结合的平行二聚体之间的关联可能导致受体聚集。这两种二聚体都掩埋了蛋白质表面的大量区域，并通过极性和非极性相互作用形成。
Activation of the cell surface receptors for tumor necrosis factor (TNF) is effected by the aggregation of cytoplasmic domains that occurs when the extracellular domains of two or three receptors bind to trimeric TNF alpha or TNF beta. The structure of the type I TNF receptor extracellular domain (sTNF-R1), crystallized in the absence of TNF, has now been determined at 2.25-Angstrom resolution. The receptor itself is an elongated molecule comprising four disulfide-rich domains in a nearly linear array. Contrary to expectations, the unliganded domains are found to associate into dimers of two distinct types, in which monomers are related by local two-fold axes of symmetry. In one case, the receptors are antiparallel to each other and associate through an interface that overlaps the TNF binding site. If intact receptors were capable of such an association, their cytoplasmic domains would be separated by over 100 Angstrom. This interaction could inhibit signaling in the absence of TNF. Parallel dimers are also observed in which the dimer interface is well separated from the TNF binding site. Associations among TNF-bound parallel dimers could cause receptor clustering. Both dimers bury substantial areas of protein surface and are formed by polar and non-polar interactions.