美国圣裘德儿童研究医院Ji Sun和美国德克萨斯大学西南医学中心Saikat Mukhopadhyay共同合作，近期取得重要工作进展。他们通过研究解析人IFT-A复合物结构为纤毛运输提供了分子见解。相关研究成果2023年2月13日在线发表于《细胞—研究》杂志上。

据介绍，鞭毛内运输（IFT）复合物，IFT-A和IFT-B，形成沿着轴突微管移动的双向链，对纤毛的组装和维持至关重要。IFT亚基的突变导致涉及多个组织的多种纤毛疾病。然而，由于没有完整复合体的高分辨率结构信息，人们对IFT复合体如何组装和介导货物运输缺乏机制理解。

研究人员发现，在有和没有TULP3的情况下，人IFT-A复合物的冷冻电镜结构，总体分辨率为3.0–3.9 Å。IFT-A采用“套索”形状，由结构上重要的锌结合域连接的核心和外周亚基相互连接。货物适配器TULP3通过其N-末端区域与IFT-A相互作用，接口界面突变会破坏货物运输。研究人员还确定了疾病突变对复合物形成和纤毛转运的分子影响。

总之，这一工作揭示了IFT-A复合体的结构，阐明了纤毛运输和IFT序列的形成机理，并使纤毛疾病的疾病突变合理化。

附：英文原文

Title: Human IFT-A complex structures provide molecular insights into ciliary transport

Author: Jiang, Meiqin, Palicharla, Vivek Reddy, Miller, Darcie, Hwang, Sun-Hee, Zhu, Hanwen, Hixson, Patricia, Mukhopadhyay, Saikat, Sun, Ji

Issue&Volume: 2023-02-13

Abstract: Intraflagellar transport (IFT) complexes, IFT-A and IFT-B, form bidirectional trains that move along the axonemal microtubules and are essential for assembling and maintaining cilia. Mutations in IFT subunits lead to numerous ciliopathies involving multiple tissues. However, how IFT complexes assemble and mediate cargo transport lacks mechanistic understanding due to missing high-resolution structural information of the holo-complexes. Here we report cryo-EM structures of human IFT-A complexes in the presence and absence of TULP3 at overall resolutions of 3.0–3.9. IFT-A adopts a “lariat” shape with interconnected core and peripheral subunits linked by structurally vital zinc-binding domains. TULP3, the cargo adapter, interacts with IFT-A through its N-terminal region, and interface mutations disrupt cargo transport. We also determine the molecular impacts of disease mutations on complex formation and ciliary transport. Our work reveals IFT-A architecture, sheds light on ciliary transport and IFT train formation, and enables the rationalization of disease mutations in ciliopathies.

DOI: 10.1038/s41422-023-00778-3

Source: https://www.nature.com/articles/s41422-023-00778-3