Structural mechanism of protein recognition by the FW domain of autophagy receptor Nbr1

• Published in: Nature communications Vol. 13; no. 1; p. 3650
• Main Authors: Zhang, Jianxiu, Wang, Ying-Ying, Pan, Zhao-Qian, Li, Yulu, Sui, Jianhua, Du, Li-Lin, Ye, Keqiong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.06.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 631/535/1258/1259; 631/80/39/2345; 631/80/39/2346; Autophagy; BRCA1 protein; Cargo; Electron microscopy; Fission; Glycine; Humanities and Social Sciences; Mannosidase; multidisciplinary; Protein structure; Proteins; Quaternary structure; Receptors; Recognition; Sandwich structures; Science; Science (multidisciplinary); Selectivity; Tryptophan; Yeast; Yeasts
• ISSN: 2041-1723; 2041-1723
• 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. Nbr1 recognizes cargos in selective autophagy. Here, authors show filamentous yeast Nbr1 binds Ams1 via an FW domain, and the cryo-EM structure reveals that Nbr1 recognizes the N-terminal di-glycine and tetrameric assembly of Ams1.