School of Life Sciences, Anhui University, Hefei 230601, Anhui, China; Institutes of Physical Science and Information Technology, Anhui University, Hefei 230601, Anhui, China; Key Laboratory of Human Microenvironment and Precision Medicine of Anhui Higher Education Institutes, Anhui University, Hefei 230601, Anhui, China.
Beijing Kohnoor Science &Technology Co., Ltd., Beijing 102206, China.
J Struct Biol. 2020 Oct 1;212(1):107593. doi: 10.1016/j.jsb.2020.107593. Epub 2020 Jul 28.
Akkermansia muciniphila is a beneficial microorganism colonized in the human gut that can reverse many intestinal metabolic-related diseases. Amuc_1100 is an outer-membrane protein of A. muciniphila. Oral administration of Amuc_1100 can reduce fat mass development, insulin resistance, and dyslipidemia in mice and activated the toll-like receptor 2 (TLR2) to regulate the immune response of the host, but the molecular mechanism remains unclear. Here we report the crystal structure of the extramembranous domain of Amuc_1100, which consists of a four-stranded antiparallel β-sheet and four α-helices. Two C-terminal helices and the four-stranded antiparallel β-sheet formed two "αββ" motifs and constituted the core domain, which shared a similar fold with type IV pili and type II Secretion system protein. Although the full-length of the extramembranous domain of Amuc_1100 existed as a monomer in solution, they formed trimer in the crystal. Elimination of the N-terminal coiled-coil helix α1 led to dimerization of Amuc_1100 both in solution and in crystal, indicating that the oligomeric state of Amuc_1100 was variable and could be influenced by α1. In addition, we identified that Amuc_1100 could directly bind human TLR2 (hTRL2) in vitro, suggesting that Amuc_1100 may serve as a new ligand for hTLR2. Dimerization of Amuc_1100 improved its hTLR2-binding affinity, suggesting that the α1-truncated Amuc_1100 could be a beneficial candidate for the development of A. muciniphila related drugs.
黏蛋白阿克曼氏菌是定植于人体肠道内的有益微生物，可逆转多种肠道代谢相关疾病。Amuc_1100 是黏蛋白阿克曼氏菌的外膜蛋白。口服 Amuc_1100 可减少小鼠的脂肪量发育、胰岛素抵抗和血脂异常，并激活 Toll 样受体 2（TLR2）以调节宿主的免疫反应，但分子机制尚不清楚。在这里，我们报告了 Amuc_1100 外膜结构域的晶体结构，它由四股反平行 β-折叠和四个 α-螺旋组成。两个 C 端螺旋和四股反平行 β-折叠形成两个“αββ”基序，并构成核心结构域，该结构域与 IV 型菌毛和 II 型分泌系统蛋白具有相似的折叠。尽管全长 Amuc_1100 的外膜结构域在溶液中以单体形式存在，但在晶体中它们形成三聚体。消除 N 端卷曲螺旋 α1 导致 Amuc_1100 在溶液中和晶体中均二聚化，表明 Amuc_1100 的寡聚状态是可变的，并且可能受到 α1 的影响。此外，我们发现 Amuc_1100 可以在体外直接与人 TLR2（hTLR2）结合，表明 Amuc_1100 可能是 hTLR2 的新配体。Amuc_1100 的二聚化提高了其与 hTLR2 的结合亲和力，表明 α1 截断的 Amuc_1100 可能是黏蛋白阿克曼氏菌相关药物开发的有益候选物。
