A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes
A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes
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DOI：
10.1126/science.288.5465.505
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发表时间：
2000-04-21
期刊：
影响因子：
56.9
通讯作者：
Teyton, L
中科院分区：
文献类型：
--
作者：
Corper, AL;Stratmann, T;Teyton, L
对鼠和人胰岛素依赖型糖尿病的易感性与主要组织相容性复合体（MHC）II类I-A或HLA-DQ等位基因（在β 57位缺乏天冬氨酸）密切相关。I-A（g7）缺乏这种天冬氨酸，并且是唯一由非肥胖糖尿病小鼠表达的II类等位基因。I-A（g7）的晶体结构在2.6埃分辨率下被确定为与来自自身抗原谷氨酸脱羧酶（CAD）65的高亲和力肽的复合物。I-A（g7）在β 57周围具有显著更宽的肽结合沟，这与其他MHC II类等位基因相比解释了不同的肽偏好。Asp（β 57）的缺失导致I-A（g7）中的含氧阴离子空穴，其可以被肽羧基残基填充，或者可能通过与T细胞受体的相互作用填充。
Susceptibility to murine and human insulin-dependent diabetes mellitus correlates strongly with major histocompatibility complex (MHC) class II I-A or HLA-DQ alleles that lack an aspartic acid at position beta 57. I-A(g7) lacks this aspartate and is the only class II allele expressed by the nonobese diabetic mouse. The crystal structure of I-A(g7) was determined at 2.6 angstrom resolution as a complex with a high-affinity peptide from the autoantigen glutamic acid decarboxylase (CAD) 65. I-A(g7) has a substantially wider peptide-binding groove around beta 57, which accounts for distinct peptide preferences compared with other MHC class II alleles. Loss of Asp(beta 57) Leads to an oxyanion hole in I-A(g7) that can be filled by peptide carboxyl residues or, perhaps, through interaction with the T cell receptor.