6gf1
From Proteopedia
The structure of the ubiquitin-like modifier FAT10 reveals a novel targeting mechanism for degradation by the 26S proteasome
Structural highlights
Function[UBD_HUMAN] Ubiquitin-like protein modifier which can be covalently attached to target protein and subsequently leads to their degradation by the 26S proteasome, in a NUB1L-dependent manner. Probably functions as a survival factor. Conjugation ability activated by UBA6. Promotes the expression of the proteasome subunit beta type-9 (PSMB9/LMP2). Regulates TNF-alpha-induced and LPS-mediated activation of the central mediator of innate immunity NF-kappa-B by promoting TNF-alpha-mediated proteasomal degradation of ubiquitinated-I-kappa-B-alpha. Required for TNF-alpha-induced p65 nuclear translocation in renal tubular epithelial cells (RTECs). May be involved in dendritic cell (DC) maturation, the process by which immature dendritic cells differentiate into fully competent antigen-presenting cells that initiate T-cell responses. Mediates mitotic non-disjunction and chromosome instability, in long-term in vitro culture and cancers, by abbreviating mitotic phase and impairing the kinetochore localization of MAD2L1 during the prometaphase stage of the cell cycle. May be involved in the formation of aggresomes when proteasome is saturated or impaired. Mediates apoptosis in a caspase-dependent manner, especially in renal epithelium and tubular cells during renal diseases such as polycystic kidney disease and Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] Publication Abstract from PubMedFAT10 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. The structure of the ubiquitin-like modifier FAT10 reveals an alternative targeting mechanism for proteasomal degradation.,Aichem A, Anders S, Catone N, Rossler P, Stotz S, Berg A, Schwab R, Scheuermann S, Bialas J, Schutz-Stoffregen MC, Schmidtke G, Peter C, Groettrup M, Wiesner S Nat Commun. 2018 Aug 20;9(1):3321. doi: 10.1038/s41467-018-05776-3. PMID:30127417[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Aichem, A | Anders, S | Berg, A | Bialas, J | Catone, N | Groettrup, M | Peter, C | Roessler, P | Scheuermann, S | Schmidtke, G | Schwab, R | Stotz, S | Wiesner, S | Degradation | Signaling protein | Ubiquitin-like
