CRL2ZER1/ZYG11B recognizes small N-terminal residues for degradation

Yao Li, Yueling Zhao, Xiaojie Yan, Chen Ye, Sara Weirich, Bing Zhang, Xiaolu Wang, Lili Song, Chenhao Jiang, Albert Jeltsch, Cheng Dong () and Wenyi Mi ()
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Yao Li: Tianjin Medical University
Yueling Zhao: Tianjin Medical University
Xiaojie Yan: Tianjin Medical University
Chen Ye: Tianjin Medical University
Sara Weirich: University of Stuttgart
Bing Zhang: Tianjin Medical University
Xiaolu Wang: Tianjin Medical University
Lili Song: Tianjin Medical University
Chenhao Jiang: Tianjin Medical University
Albert Jeltsch: University of Stuttgart
Cheng Dong: Tianjin Medical University
Wenyi Mi: Tianjin Medical University

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract N-degron pathway plays an important role in the protein quality control and maintenance of cellular protein homeostasis. ZER1 and ZYG11B, the substrate receptors of the Cullin 2-RING E3 ubiquitin ligase (CRL2), recognize N-terminal (Nt) glycine degrons and participate in the Nt-myristoylation quality control through the Gly/N-degron pathway. Here we show that ZER1 and ZYG11B can also recognize small Nt-residues other than glycine. Specifically, ZER1 binds better to Nt-Ser, -Ala, -Thr and -Cys than to -Gly, while ZYG11B prefers Nt-Gly but also has the capacity to recognize Nt-Ser, -Ala and -Cys in vitro. We found that Nt-Ser, -Ala and -Cys undergo Nt-acetylation catalyzed by Nt-acetyltransferase (NAT), thereby shielding them from recognition by ZER1/ZYG11B in cells. Instead, ZER1/ZYG11B readily targets a selection of small Nt-residues lacking Nt-acetylation for degradation in NAT-deficient cells, implicating its role in the Nt-acetylation quality control. Furthermore, we present the crystal structures of ZER1 and ZYG11B bound to various small Nt-residues and uncover the molecular mechanism of non-acetylated substrate recognition by ZER1 and ZYG11B.

Date: 2022
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DOI: 10.1038/s41467-022-35169-6

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