Misaghi Shahram, Sun Zhen-Yu J, Stern Patrick, Gaudet Rachelle, Wagner Gerhard, Ploegh Hidde
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Virol. 2004 Jan;78(1):413-23. doi: 10.1128/jvi.78.1.413-423.2004.
Human cytomegalovirus (HCMV) unique short region 3 (US3) protein, a type I membrane protein, prevents maturation of class I major histocompatibility complex (MHC) molecules by retaining them in the endoplasmic reticulum (ER) and thus helps inhibit antigen presentation to cytotoxic T cells. US3 molecules bind to class I MHC molecules in a transient fashion but retain them very efficiently in the ER nonetheless. The US3 luminal domain is responsible for ER retention of US3 itself, while both the US3 luminal and transmembrane domains are necessary for retaining class I MHC in the ER. We have expressed the luminal domain of US3 molecule in Escherichia coli and analyzed its secondary structure by using nuclear magnetic resonance. We then predicted the US3 tertiary structure by modeling it based on the US2 structure. Unlike the luminal domain of US2, the US3 luminal domain does not obviously interact with class I MHC molecules. The luminal domain of US3 dynamically oligomerizes in vitro and full-length US3 molecules associate with each other in vivo. We present a model depicting how dynamic oligomerization of US3 may enhance its ability to retain class I molecules within the ER.
人巨细胞病毒（HCMV）独特短区域3（US3）蛋白是一种I型膜蛋白，它通过将I类主要组织相容性复合体（MHC）分子滞留在内质网（ER）中，阻止其成熟，从而有助于抑制向细胞毒性T细胞的抗原呈递。US3分子以瞬时方式与I类MHC分子结合，但仍能非常有效地将它们滞留在ER中。US3腔内结构域负责US3自身在内质网中的滞留，而US3腔内结构域和跨膜结构域对于将I类MHC滞留在ER中都是必需的。我们已经在大肠杆菌中表达了US3分子的腔内结构域，并使用核磁共振分析了其二级结构。然后，我们通过基于US2结构对其进行建模来预测US3的三级结构。与US2的腔内结构域不同，US3的腔内结构域与I类MHC分子没有明显的相互作用。US3的腔内结构域在体外动态寡聚，全长US3分子在体内相互结合。我们提出了一个模型，描述了US3的动态寡聚如何增强其将I类分子滞留在ER内的能力。
