Solution structure of a Bcl-2 homolog from Kaposi sarcoma virus

Kaposi sarcoma-associated herpes virus (KSHV) contains a gene that has functional and sequence homology to the apoptotic Bcl-2 family of proteins [Sarid, R., Sato, T., Bohenzky, R. A., Russo, J. J. & Chang, Y. (1997) Nat. Med. 3, 293–298]. The viral Bcl-2 protein promotes survival of infected cells and may contribute to the development of Kaposi sarcoma tumors [Boshoff, C. & Chang, Y. (2001) Annu. Rev. Med. 52, 453–470]. Here we describe the solution structure of the viral Bcl-2 homolog from KSHV. Comparison of the KSHV Bcl-2 structure to that of Bcl-2 and Bcl-x(L) shows that although the overall fold is the same, there are key differences in the lengths of the helices and loops. Binding studies on peptides derived from the Bcl-2 homology region 3 of proapoptotic family members indicate that the specificity of the viral protein is very different from what was previously observed for Bcl-x(L) and Bcl-2, suggesting that the viral protein has evolved to have a different mechanism of action than the host proteins.

卡波西肉瘤相关疱疹病毒（Kaposi sarcoma-associated herpes virus, KSHV）携带有一个在功能与序列上均与凋亡性Bcl-2家族蛋白具有同源性的基因[Sarid, R., Sato, T., Bohenzky, R. A., Russo, J. J. & Chang, Y. (1997) Nat. Med. 3, 293–298]。该病毒编码的Bcl-2蛋白可促进受感染细胞的存活，并可能参与卡波西肉瘤的发生发展[Boshoff, C. & Chang, Y. (2001) Annu. Rev. Med. 52, 453–470]。本文报道了KSHV来源的病毒Bcl-2同源蛋白的溶液结构。将KSHV Bcl-2的结构与Bcl-2及Bcl-x(L)的结构进行比对后发现，尽管二者整体折叠模式一致，但在螺旋区与环区的长度上存在关键差异。针对促凋亡家族成员的Bcl-2同源结构域3（Bcl-2 homology region 3, BH3）衍生肽的结合实验表明，该病毒蛋白的结合特异性与此前在Bcl-x(L)和Bcl-2中观测到的结果存在显著差异，这提示该病毒蛋白已演化出与宿主同源蛋白截然不同的作用机制。