The structure of the ubiquitin-like modifier FAT10 reveals an alternative targeting mechanism for proteasomal degradation

Annette Aichem, Samira Anders, Nicola Catone, Philip Rößler, Sophie Stotz, Andrej Berg, Ricarda Schwab, Sophia Scheuermann, Johanna Bialas, Mira C. Schütz-Stoffregen, Gunter Schmidtke, Christine Peter, Marcus Groettrup () and Silke Wiesner ()
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Annette Aichem: University of Konstanz
Samira Anders: Max Planck Institute for Developmental Biology
Nicola Catone: Biotechnology Institute Thurgau at the University of Konstanz
Philip Rößler: Max Planck Institute for Developmental Biology
Sophie Stotz: Max Planck Institute for Developmental Biology
Andrej Berg: University of Konstanz
Ricarda Schwab: University of Konstanz
Sophia Scheuermann: University of Konstanz
Johanna Bialas: University of Konstanz
Mira C. Schütz-Stoffregen: Max Planck Institute for Developmental Biology
Gunter Schmidtke: University of Konstanz
Christine Peter: University of Konstanz
Marcus Groettrup: University of Konstanz
Silke Wiesner: Max Planck Institute for Developmental Biology

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract FAT10 is a ubiquitin-like modifier that directly targets proteins for proteasomal degradation. Here, we report the high-resolution structures of the two individual ubiquitin-like domains (UBD) of FAT10 that are joined by a flexible linker. While the UBDs of FAT10 show the typical ubiquitin-fold, their surfaces are entirely different from each other and from ubiquitin explaining their unique binding specificities. Deletion of the linker abrogates FAT10-conjugation while its mutation blocks auto-FAT10ylation of the FAT10-conjugating enzyme USE1 but not bulk conjugate formation. FAT10- but not ubiquitin-mediated degradation is independent of the segregase VCP/p97 in the presence but not the absence of FAT10’s unstructured N-terminal heptapeptide. Stabilization of the FAT10 UBDs strongly decelerates degradation suggesting that the intrinsic instability of FAT10 together with its disordered N-terminus enables the rapid, joint degradation of FAT10 and its substrates without the need for FAT10 de-conjugation and partial substrate unfolding.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05776-3

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DOI: 10.1038/s41467-018-05776-3

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