6GF2

The structure of the ubiquitin-like modifier FAT10 reveals a novel targeting mechanism for degradation by the 26S proteasome

Summary for 6GF2

• Entry DOI: 10.2210/pdb6gf2/pdb
• NMR Information: BMRB: 27466
• Descriptor: Ubiquitin D (1 entity in total)
• Functional Keywords: fat10, ubiquitin-like modifier, proteasome, degradation, immune system
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 9263.70

Authors

Aichem, A.,Anders, S.,Catone, N.,Roessler, P.,Stotz, S.,Berg, A.,Schwab, R.,Scheuermann, S.,Bialas, J.,Schmidtke, G.,Peter, C.,Groettrup, M.,Wiesner, S. (deposition date: 2018-04-29, release date: 2018-08-08, Last modification date: 2024-06-19)

Primary citation

Aichem, A.,Anders, S.,Catone, N.,Stotz, S.,Berg, A.,Schwab, R.,Scheuermann, S.,Bialas, J.,Schutz-Stoffregen, M.C.,Schmidtke, G.,Peter, C.,Groettrup, M.,Wiesner, S.
The structure of the ubiquitin-like modifier FAT10 reveals an alternative targeting mechanism for proteasomal degradation.
Nat Commun, 9:3321-3321, 2018

PubMed 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.

PubMed: 30127417
DOI: 10.1038/s41467-018-05776-3

Experimental method

SOLUTION NMR