7pyv | pdb_00007pyv
Crystal structure of human UBA6 in complex with the ubiquitin-like modifier FAT10
Structural highlights
Disease[UBA1_HUMAN] X-linked distal arthrogryposis multiplex congenita. The disease is caused by mutations affecting the gene represented in this entry. Function[UBA1_HUMAN] Catalyzes the first step in ubiquitin conjugation to mark cellular proteins for degradation through the ubiquitin-proteasome system. Activates ubiquitin by first adenylating its C-terminal glycine residue with ATP, and thereafter linking this residue to the side chain of a cysteine residue in E1, yielding a ubiquitin-E1 thioester and free AMP. Essential for the formation of radiation-induced foci, timely DNA repair and for response to replication stress. Promotes the recruitment of TP53BP1 and BRCA1 at DNA damage sites.[1] [UBA6_HUMAN] Activates ubiquitin by first adenylating its C-terminal glycine residue with ATP, and thereafter linking this residue to the side chain of a cysteine residue in E1, yielding a ubiquitin-E1 thioester and free AMP. Specific for ubiquitin, does not activate ubiquitin-like peptides. Differs from UBE1 in its specificity for substrate E2 charging. Does not charge cell cycle E2s, such as CDC34. Essential for embryonic development. Required for UBD/FAT10 conjugation. Isoform 2 may play a key role in ubiquitin system and may influence spermatogenesis and male fertility.[2] [3] [4] Publication Abstract from PubMedThe covalent modification of target proteins with ubiquitin or ubiquitin-like modifiers is initiated by E1 activating enzymes, which typically transfer a single modifier onto cognate conjugating enzymes. UBA6 is an unusual E1 since it activates two highly distinct modifiers, ubiquitin and FAT10. Here, we report crystal structures of UBA6 in complex with either ATP or FAT10. In the UBA6-FAT10 complex, the C-terminal domain of FAT10 binds to where ubiquitin resides in the UBA1-ubiquitin complex, however, a switch element ensures the alternate recruitment of either modifier. Simultaneously, the N-terminal domain of FAT10 interacts with the 3-helix bundle of UBA6. Site-directed mutagenesis identifies residues permitting the selective activation of either ubiquitin or FAT10. These results pave the way for studies investigating the activation of either modifier by UBA6 in physiological and pathophysiological settings. Structures of UBA6 explain its dual specificity for ubiquitin and FAT10.,Truongvan N, Li S, Misra M, Kuhn M, Schindelin H Nat Commun. 2022 Aug 15;13(1):4789. doi: 10.1038/s41467-022-32040-6. PMID:35970836[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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