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ADP-ribosylserine hydrolase ARH3 of Latimeria chalumnae in complex with alpha-1-O-methyl-ADP-ribose (meADPr)
Structural highlights
FunctionADPRS_LATCH ADP-ribosylhydrolase that preferentially hydrolyzes the scissile alpha-O-linkage attached to the anomeric C1 position of ADP-ribose and acts on different substrates, such as proteins ADP-ribosylated on serine and threonine, free poly(ADP-ribose) and O-acetyl-ADP-D-ribose (PubMed:30472116). Specifically acts as a serine mono-ADP-ribosylhydrolase by mediating the removal of mono-ADP-ribose attached to serine residues on proteins, thereby playing a key role in DNA damage response (PubMed:30472116). Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (By similarity). Does not hydrolyze ADP-ribosyl-arginine, -cysteine, -diphthamide, or -asparagine bonds (By similarity). Also able to degrade protein free poly(ADP-ribose), which is synthesized in response to DNA damage: free poly(ADP-ribose) acts as a potent cell death signal and its degradation by ADPRHL2 protects cells from poly(ADP-ribose)-dependent cell death, a process named parthanatos (PubMed:30472116). Also hydrolyzes free poly(ADP-ribose) in mitochondria (By similarity). Specifically digests O-acetyl-ADP-D-ribose, a product of deacetylation reactions catalyzed by sirtuins (By similarity). Specifically degrades 1-O-acetyl-ADP-D-ribose isomer, rather than 2-O-acetyl-ADP-D-ribose or 3-O-acetyl-ADP-D-ribose isomers (By similarity).[UniProtKB:Q9NX46][1] Publication Abstract from PubMedPoly(ADP-ribosyl)ation (PAR) is a versatile and complex posttranslational modification composed of repeating units of ADP-ribose arranged into linear or branched polymers. This scaffold is linked to the regulation of many of cellular processes including the DNA damage response, alteration of chromatin structure and Wnt signalling. Despite decades of research, the principles and mechanisms underlying all steps of PAR removal remain actively studied. In this work, we synthesise well-defined PAR branch point molecules and demonstrate that PARG, but not ARH3, can resolve this distinct PAR architecture. Structural analysis of ARH3 in complex with dimeric ADP-ribose as well as an ADP-ribosylated peptide reveal the molecular basis for the hydrolysis of linear and terminal ADP-ribose linkages. We find that ARH3-dependent hydrolysis requires both rearrangement of a catalytic glutamate and induction of an unusual, square-pyramidal magnesium coordination geometry. Mechanistic insights into the three steps of poly(ADP-ribosylation) reversal.,Rack JGM, Liu Q, Zorzini V, Voorneveld J, Ariza A, Honarmand Ebrahimi K, Reber JM, Krassnig SC, Ahel D, van der Marel GA, Mangerich A, McCullagh JSO, Filippov DV, Ahel I Nat Commun. 2021 Jul 28;12(1):4581. doi: 10.1038/s41467-021-24723-3. PMID:34321462[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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