Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Department of Microbiology, University of Illinois, Urbana, IL 61801, USA.
Structure. 2019 Jun 4;27(6):1029-1033.e3. doi: 10.1016/j.str.2019.03.015. Epub 2019 Apr 18.
Microrchidia 3 (MORC3), a human ATPase linked to several autoimmune disorders, has been characterized both as a negative and positive regulator of influenza A virus. Here, we report that the CW domain of MORC3 (MORC3-CW) is targeted by the C-terminal tail of the influenza H3N2 protein NS1. The crystal structure of the MORC3-CW:NS1 complex shows that NS1 occupies the same binding site in CW that is normally occupied by histone H3, a physiological ligand of MORC3-CW. Comparable binding affinities of MORC3-CW to H3 and NS1 peptides and to the adjacent catalytic ATPase domain suggest that the viral protein can compete with the host histone for the association with CW, releasing MORC3 autoinhibition and activating the catalytic function of MORC3. Our structural, biochemical, and cellular analyses suggest that MORC3 might affect the infectivity of influenza virus and therefore has a role in cell immune response.
微体 3（MORC3）是一种与人的 ATP 酶相关联的蛋白，与多种自身免疫性疾病有关，其被鉴定为甲型流感病毒的负调控因子和正调控因子。在这里，我们报告称，MORC3 的 CW 结构域（MORC3-CW）是流感 H3N2 蛋白 NS1 的 C 端尾部的靶标。MORC3-CW:NS1 复合物的晶体结构表明，NS1 占据了 CW 中通常被 MORC3-CW 的生理配体组蛋白 H3 占据的相同结合位点。MORC3-CW 对 H3 和 NS1 肽以及相邻的催化 ATP 酶结构域的可比结合亲和力表明，该病毒蛋白可以与宿主组蛋白竞争与 CW 的结合，从而释放 MORC3 的自动抑制并激活 MORC3 的催化功能。我们的结构、生化和细胞分析表明，MORC3 可能影响流感病毒的感染力，因此在细胞免疫反应中具有作用。
