Assembly and structural properties of glucocorticoid-induced TNF receptor ligand: Implications for function
Assembly and structural properties of glucocorticoid-induced TNF receptor ligand: Implications for function
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DOI：
10.1073/pnas.0709264104
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发表时间：
2007-12-04
影响因子：
11.1
通讯作者：
Almo, Steven C.
中科院分区：
文献类型：
--
作者：
Chattopadhyay, Kausik;Ramagopalt, Udupi A.;Almo, Steven C.
糖皮质激素诱导的TNF受体配体（GITRL）是最近发现的TNF家族成员，可在效应和调节性T细胞上与其受体GITR结合，并产生积极的共刺激信号，涉及广泛的T细胞功能。结构分析表明，人类GITRL （hGITRL）外畴自组装成具有稀疏单体界面的非典型扩展同源三聚体。与小亚基间界面一致，hGITRL在溶液中表现出相对较弱的三聚化倾向，并表现出其他TNF家族成员未报道的单体-三聚体平衡。这种独特的组装行为对hGITRL- gitr信号传导有直接的影响，因为可溶性hGITRL外结构域的强制三聚化导致其受体结合亲和力增加了大约100倍，并增强了共刺激活性。这种动态平衡的结果是亲和度的明显降低，这可能代表了一种机制，通过hGITRL-GITR途径实现生物学上最优的信号水平，而不是可达到的最大水平。
Glucocorticoid-induced TNF receptor ligand (GITRL), a recently identified member of the TNF family, binds to its receptor GITR on both effector and regulatory T cells and generates positive costimulatory signals implicated in a wide range of T cell functions. Structural analysis reveals that the human GITRL (hGITRL) ectodomain self-assembles into an atypical expanded homotrimer with sparse monomer-monomer interfaces. Consistent with the small intersubunit interfaces, hGITRL exhibits a relatively weak tendency to trimerize in solution and displays a monomer-trimer equilibrium not reported for other TNF family members. This unique assembly behavior has direct implications for hGITRL-GITR signaling, because enforced trimerization of soluble hGITRL ectodomain results in an approximate to 100-fold increase in its receptor binding affinity and also in enhanced costimulatory activity. The apparent reduction in affinity that is the consequence of this dynamic equilibrium may represent a mechanism to realize the biologically optimal level of signaling through the hGITRL-GITR pathway, as opposed to the maximal achievable level.