Orphan quality control by an SCF ubiquitin ligase directed to pervasive C-degrons

Ka-Yiu Edwin Kong (), Susmitha Shankar, Frank Rühle and Anton Khmelinskii ()
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Ka-Yiu Edwin Kong: Institute of Molecular Biology (IMB)
Susmitha Shankar: Institute of Molecular Biology (IMB)
Frank Rühle: Institute of Molecular Biology (IMB)
Anton Khmelinskii: Institute of Molecular Biology (IMB)

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Selective protein degradation typically involves substrate recognition via short linear motifs known as degrons. Various degrons can be found at protein termini from bacteria to mammals. While N-degrons have been extensively studied, our understanding of C-degrons is still limited. Towards a comprehensive understanding of eukaryotic C-degron pathways, here we perform an unbiased survey of C-degrons in budding yeast. We identify over 5000 potential C-degrons by stability profiling of random peptide libraries and of the yeast C‑terminome. Combining machine learning, high-throughput mutagenesis and genetic screens reveals that the SCF ubiquitin ligase targets ~40% of degrons using a single F-box substrate receptor Das1. Although sequence-specific, Das1 is highly promiscuous, recognizing a variety of C-degron motifs. By screening for full-length substrates, we implicate SCFDas1 in degradation of orphan protein complex subunits. Altogether, this work highlights the variety of C-degron pathways in eukaryotes and uncovers how an SCF/C-degron pathway of broad specificity contributes to proteostasis.

Date: 2023
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DOI: 10.1038/s41467-023-44096-z

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