The complementarity-determining region-like loops of CD8α interact differently with β2-microglobulin of the class I molecules H-2Kb and thymic leukemia antigen, while similarly with their α3 domains
The complementarity-determining region-like loops of CD8α interact differently with β2-microglobulin of the class I molecules H-2Kb and thymic leukemia antigen, while similarly with their α3 domains
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DOI：
10.4049/jimmunol.168.8.3881
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发表时间：
2002-04-15
影响因子：
4.4
通讯作者：
Kavathas, PB
中科院分区：
文献类型：
--
作者：
Devine, L;Rogozinski, L;Kavathas, PB
鼠CD 8糖蛋白与经典的MHC I类分子和一些非经典分子相互作用，包括胸腺白血病Ag（TL）。TL优先结合CD 8 α α同源二聚体，亲和力比H-2 K（B）I类分子高10倍。为了理解这种差异的分子基础，我们创建了一组CD 8 α突变体，并测试了CD 8 aa同源二聚体与H-2 K（B）四聚体和TL四聚体结合的能力。位于互补决定区样环上的三个CD 8残基中的突变与MHC I类的α 3结构域中带负电荷的环接触，大大降低了与两种四聚体的结合。由于TL和H-2K（B）I类序列在MHC 1类的α 3结构域中高度保守，这表明CD 8以类似的方式接触TL和H-2K（B）的α 3结构域。相反，参与与β 2-微球蛋白接触的CD 8 β链A和B残基突变影响与H-2 K（B）四聚体的相互作用，但不影响TL四聚体。因此，TL与CD 8相互作用的方向似乎不同于H-2 K（B）。TL与CD 8 α α独特的高亲和力结合最可能是TL和H-2 K（B）之间α 3结构域的氨基酸差异的结果，特别是在位置198（K至D）和228（M至T），其是CD 8 α α-H-2 K（B）共晶体中的接触残基。
The murine CD8 glycoprotein interacts with both classical MHC class I molecules and some nonclassical molecules, including the thymic leukemia Ag (TL). TL binds preferentially to CD8alphaalpha homodimers with a 10-fold higher affinity than H-2K(b) class I molecules. To understand the molecular basis for this difference, we created a panel of CD8alpha mutants and tested the ability of the CD8aa homodimers to bind to H-2K(b) tetramers and TL tetramers. Mutations in three CD8 residues located on the complementarity-determining region-like loops contacting the negatively charged loop in the alpha3 domain of MHC class I greatly reduced binding to both tetramers. Because TL and H-2K(b) class I sequences are highly conserved in the a3 domain of MHC class 1, this suggests that CD8 contacts the alpha3 domain of TL and H-2K(b) in a similar manner. In contrast, mutations in residues on the A and B beta strands of CD8 that are involved in contact with beta(2)-microglobulin affected interaction with the H-2K(b) tetramer, but not the TL tetramer. Therefore, the orientation of interaction of TL with CD8 appears to be different from that of H-2K(b). The unique high affinity binding of TL with CD8alphaalpha is most likely a result of amino acid differences in the alpha3 domain between TL and H-2K(b), particularly at positions 198 (K to D) and 228 (M to T), which are contact residues in the CD8alphaalpha-H-2K(b) cocrystal.