2 ANGSTROM CRYSTAL-STRUCTURE OF AN EXTRACELLULAR FRAGMENT OF HUMAN CD40 LIGAND
2 ANGSTROM CRYSTAL-STRUCTURE OF AN EXTRACELLULAR FRAGMENT OF HUMAN CD40 LIGAND
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DOI：
10.1016/s0969-2126(01)00239-8
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发表时间：
1995-10-15
期刊：
影响因子：
5.7
通讯作者：
THOMAS, D
中科院分区：
文献类型：
--
作者：
KARPUSAS, M;HSU, YM;THOMAS, D
背景资料：CD 40配体（CD 40 L）是肿瘤坏死因子（TNF）蛋白家族的成员，在活化的T细胞表面瞬时表达。CD 40 L与在B细胞表面上表达的CD 40的结合提供了导致抗体同种型转换、细胞凋亡调节以及B细胞增殖和分化的关键且独特的细胞活化途径。自然发生的突变的CD 40 L的结果在临床高IgM综合征，其特征是不能产生免疫球蛋白的IgG，伊加和IgE isotype.Results：我们已经确定了晶体结构的可溶性细胞外片段的人CD 40 L 2埃分辨率和R因子为21.8%。虽然该分子形成的三聚体类似于TNF家族的其他成员，如TNF α和α-光敏素，并表现出类似的整体折叠，有相当大的差异，在几个环，包括那些预测参与CD 40结合。结论：该结构表明，大多数高IgM综合征突变影响分子的折叠和稳定性，而不是直接影响CD 40结合位点。尽管高IgM综合征突变分散在一级序列中，但它们中的很大一部分聚集在表面环附近的空间中，靠近预测的CD 40结合位点。
Background: The CD40 ligand (CD40L) is a member of the tumor necrosis factor (TNF) family of proteins and is transiently expressed on the surface of activated T cells. The binding of CD40L to CD40, which is expressed on the surface of B cells, provides a critical and unique pathway of cellular activation resulting in antibody isotype switching, regulation of apoptosis, and B cell proliferation and differentiation. Naturally occurring mutations of CD40L result in the clinical hyper-IgM syndrome, characterized by an inability to produce immunoglobulins of the IgG, IgA and IgE isotypes.Results: We have determined the crystal structure of a soluble extracellular fragment of human CD40L to 2 Angstrom resolution and with an R factor of 21.8%. Although the molecule forms a trimer similar to that found for other members of the TNF family, such as TNF alpha and lymphotoxin-alpha, and exhibits a similar overall fold, there are considerable differences in several loops including those predicted to be involved in CD40 binding.Conclusions: The structure suggests that most of the hyper-IgM syndrome mutations affect the folding and stability of the molecule rather than the CD40-binding site directly. Despite the bet that the hyper-IgM syndrome mutations are dispersed in the primary sequence, a large fraction of them are clustered in space in the vicinity of a surface loop, close to the predicted CD40-binding site.