Abteilung Physikalische Biochemie, Max-Planck-Institut für molekulare Physiologie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
Traffic. 2011 Jul;12(7):867-77. doi: 10.1111/j.1600-0854.2011.01205.x. Epub 2011 May 5.
The human immunodeficiency virus 1 (HIV-1) Nef protein is a pathogenicity factor required for effective progression to AIDS, which modulates host cell signaling pathways and T-cell receptor internalization. We have determined the crystal structure of Nef, allele SF2, in complex with an engineered SH3 domain of human Hck showing unnaturally tight binding and inhibitory potential toward Nef. This complex provides the most complete Nef structure described today, and explains the structural basis of the high affinity of this interaction. Intriguingly, the 33-residue C-terminal flexible loop is resolved in the structure by its interactions with a highly conserved hydrophobic groove on the core domain of an adjacent Nef molecule. The loop mediates the interaction of Nef with the cellular adaptor protein machinery for the stimulated internalization of surface receptors. The endocytic dileucine-based sorting motif is exposed at the tip of the acidic loop, giving the myristoylated Nef protein a distinctly dipolar character. The intermolecular domain assembly of Nef provides insights into a possible regulation mechanism for cargo trafficking.
人类免疫缺陷病毒 1（HIV-1）Nef 蛋白是导致艾滋病有效进展的致病性因素，它调节宿主细胞信号通路和 T 细胞受体内化。我们已经确定了 Nef、SF2 等位基因与工程化的人类 Hck SH3 结构域的复合物的晶体结构，该结构域显示出异常紧密的结合和对 Nef 的抑制潜力。该复合物提供了迄今为止描述的最完整的 Nef 结构，解释了这种相互作用高亲和力的结构基础。有趣的是，33 个残基的 C 末端柔性环通过与相邻 Nef 分子核心结构域上高度保守的疏水槽相互作用在结构中得到解析。该环介导了 Nef 与细胞衔接蛋白机器的相互作用，用于刺激表面受体的内化。基于二亮氨酸的内吞分选基序暴露在酸性环的顶端，使豆蔻酰化的 Nef 蛋白具有明显的偶极特性。Nef 的分子间结构域组装提供了对货物运输的可能调节机制的深入了解。
