Naismith J H, Devine T Q, Brandhuber B J, Sprang S R
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas 75235-9050, USA.
J Biol Chem. 1995 Jun 2;270(22):13303-7. doi: 10.1074/jbc.270.22.13303.
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-A 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 A. 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.
肿瘤坏死因子（TNF）细胞表面受体的激活是由细胞质结构域的聚集所介导的，当两到三个受体的细胞外结构域与三聚体TNFα或TNFβ结合时，就会发生这种聚集。现已确定在无TNF情况下结晶的I型TNF受体细胞外结构域（sTNF-R1）的结构，分辨率为2.25埃。该受体本身是一个细长分子，由四个富含二硫键的结构域以近乎线性的排列组成。与预期相反，未结合配体的结构域被发现会形成两种不同类型的二聚体，其中单体通过局部二重对称轴相关联。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相互作用。如果完整的受体能够发生这种相互作用，它们的细胞质结构域将被分隔超过100埃。这种相互作用可能在无TNF时抑制信号传导。还观察到平行二聚体，其中二聚体界面与TNF结合位点分隔良好。TNF结合的平行二聚体之间的相互作用可能导致受体聚集。两种二聚体都掩埋了相当大的蛋白质表面区域，并且由极性和非极性相互作用形成。
