Structural insights into the assembly of the agrin/LRP4/MuSK signaling complex.
Structural insights into the assembly of the agrin/LRP4/MuSK signaling complex.
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DOI：
10.1073/pnas.2300453120
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发表时间：
2023-06-06
影响因子：
11.1
通讯作者：
Bai XC
中科院分区：
文献类型：
--
作者：
Xie T;Xu G;Liu Y;Quade B;Lin W;Bai XC
MuSK 受体在控制神经肌肉接头的形成中发挥重要作用。 MuSK 的激活不仅需要其配体集聚蛋白，还需要其辅助受体 LRP4。我们以 3.8 Å 的整体分辨率确定了 1:1:1 agrin/LRP4/MuSK 复合物的冷冻电镜结构。该结构表明，弧形 LRP4 充当“夹子”，将 agrin 和 MuSK 紧密结合在一起，从而显着增加它们的结合亲和力。因此，我们的结构揭示了为什么 LRP4 对于 MuSK 功能至关重要，为 MuSK 信号复合物的组装机制提供了见解。 MuSK 是一种受体酪氨酸激酶 (RTK)，在神经肌肉接头的形成和维护中发挥重要作用。与 RTK 家族的大多数成员不同，MuSK 激活不仅需要其同源配体 agrin，还需要其辅助受体 LRP4。然而，agrin 和 LRP4 如何共同激活 MuSK 仍不清楚。在这里，我们报道了化学计量为 1:1:1 的 agrin/LRP4/MuSK 细胞外三元复合物的冷冻电镜结构。这种结构揭示了弧形LRP4同时将集聚蛋白和MuSK招募到其中央腔，从而促进集聚蛋白和MuSK之间的直接相互作用。因此，我们的冷冻电镜分析揭示了 agrin/LRP4/MuSK 信号复合物的组装机制，并揭示了 MuSK 受体如何通过 agrin 和 LRP4 的同时结合而被激活。
MuSK receptor plays essential roles in controlling the formation of the neuromuscular junction. The activation of MuSK requires not only its ligand agrin but also its coreceptor LRP4. We determined the cryo-EM structure of 1:1:1 agrin/LRP4/MuSK complex at overall 3.8 Å resolution. This structure shows that the arc-shaped LRP4 acts as a “clamp” that holds agrin and MuSK closely and thereby significantly increases their binding affinity. Thus, our structure reveals why LRP4 is essential for MuSK function, providing insights into the assembly mechanism of MuSK signaling complex. MuSK is a receptor tyrosine kinase (RTK) that plays essential roles in the formation and maintenance of the neuromuscular junction. Distinct from most members of RTK family, MuSK activation requires not only its cognate ligand agrin but also its coreceptor LRP4. However, how agrin and LRP4 coactivate MuSK remains unclear. Here, we report the cryo-EM structure of the extracellular ternary complex of agrin/LRP4/MuSK in a stoichiometry of 1:1:1. This structure reveals that arc-shaped LRP4 simultaneously recruits both agrin and MuSK to its central cavity, thereby promoting a direct interaction between agrin and MuSK. Our cryo-EM analyses therefore uncover the assembly mechanism of agrin/LRP4/MuSK signaling complex and reveal how MuSK receptor is activated by concurrent binding of agrin and LRP4.
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影响因子：
16.2
作者：
Zhang B;Luo S;Wang Q;Suzuki T;Xiong WC;Mei L
通讯作者：
Mei L
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
7.7
作者：
Huang, Yongjian;Bharill, Shashank;Kuriyan, John
通讯作者：
Kuriyan, John
影响因子：
16.2
作者：
Gillespie, SKH;Balasubramanian, S;Huganir, RL
通讯作者：
Huganir, RL
影响因子：
5.6
作者：
Stiegler, Amy L.;Burden, Steven J.;Hubbard, Stevan R.
通讯作者：
Hubbard, Stevan R.