Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Nat Commun. 2022 Jun 25;13(1):3650. doi: 10.1038/s41467-022-31439-5.
Neighbor of BRCA1 (Nbr1) is a conserved autophagy receptor that provides cargo selectivity to autophagy. The four-tryptophan (FW) domain is a signature domain of Nbr1, but its exact function remains unclear. Here, we show that Nbr1 from the filamentous fungus Chaetomium thermophilum uses its FW domain to bind the α-mannosidase Ams1, a cargo of selective autophagy in both budding yeast and fission yeast, and delivers Ams1 to the vacuole by conventional autophagy in heterologous fission yeast. The structure of the Ams1-FW complex was determined at 2.2 Å resolution by cryo-electron microscopy. The FW domain adopts an immunoglobulin-like β-sandwich structure and recognizes the quaternary structure of the Ams1 tetramer. Notably, the N-terminal di-glycine of Ams1 is specifically recognized by a conserved pocket of the FW domain. The FW domain becomes degenerated in fission yeast Nbr1, which binds Ams1 with a ZZ domain instead. Our findings illustrate the protein binding mode of the FW domain and reveal the versatility of Nbr1-mediated cargo recognition.
BRCA1 相关蛋白 1（Nbr1）的近邻是一种保守的自噬受体，可为自噬提供货物的选择性。四色氨酸（FW）结构域是 Nbr1 的特征结构域，但它的确切功能尚不清楚。在这里，我们展示了嗜热毛壳菌（Chaetomium thermophilum）的 Nbr1 利用其 FW 结构域结合α-甘露糖苷酶 Ams1，该蛋白是出芽酵母和裂殖酵母中选择性自噬的货物，并通过异源裂殖酵母中的常规自噬将 Ams1 递送至液泡。通过冷冻电镜确定了 Ams1-FW 复合物的结构，分辨率为 2.2 Å。FW 结构域采用免疫球蛋白样β-三明治结构，并识别 Ams1 四聚体的四级结构。值得注意的是，Ams1 的 N 端双甘氨酸被 FW 结构域的保守口袋特异性识别。裂殖酵母 Nbr1 中的 FW 结构域发生退化，转而与 ZZ 结构域结合 Ams1。我们的研究结果说明了 FW 结构域的蛋白结合模式，并揭示了 Nbr1 介导的货物识别的多功能性。
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