Structure of human ADP-ribosyl-acceptor hydrolase 3 bound to ADP-ribose reveals a conformational switch that enables specific substrate recognition

ADP-ribosyl-acceptor hydrolase 3 (ARH3) plays important roles in regulation of poly(ADP-ribosyl)ation, a reversible post-translational modification, and in maintenance of genomic integrity. ARH3 degrades poly(ADP-ribose) to protect cells from poly(ADP-ribose)–dependent cell death, reverses serine mo...

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Published in:The Journal of biological chemistry 2018-08, Vol.293 (32), p.12350-12359
Main Authors: Pourfarjam, Yasin, Ventura, Jessica, Kurinov, Igor, Cho, Ahra, Moss, Joel, Kim, In-Kwon
Format: Article
Language:English
Subjects:
Adenosine Diphosphate Ribose - chemistry
Adenosine Diphosphate Ribose - metabolism
ADP-ribosylation
Amino Acid Sequence
ARH3
Catalysis
Catalytic Domain
conformational change
Crystallography, X-Ray
Glycoside Hydrolases - chemistry
Glycoside Hydrolases - metabolism
Humans
hydrolase
Hydrolysis
Models, Molecular
PARP1
Protein Conformation
Protein Structure and Folding
Sequence Homology
structural biology
Substrate Specificity
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Summary:ADP-ribosyl-acceptor hydrolase 3 (ARH3) plays important roles in regulation of poly(ADP-ribosyl)ation, a reversible post-translational modification, and in maintenance of genomic integrity. ARH3 degrades poly(ADP-ribose) to protect cells from poly(ADP-ribose)–dependent cell death, reverses serine mono(ADP-ribosyl)ation, and hydrolyzes O-acetyl-ADP-ribose, a product of Sirtuin-catalyzed histone deacetylation. ARH3 preferentially hydrolyzes O-linkages attached to the anomeric C1″ of ADP-ribose; however, how ARH3 specifically recognizes and cleaves structurally diverse substrates remains unknown. Here, structures of full-length human ARH3 bound to ADP-ribose and Mg2+, coupled with computational modeling, reveal a dramatic conformational switch from closed to open states that enables specific substrate recognition. The glutamate flap, which blocks substrate entrance to Mg2+ in the unliganded closed state, is ejected from the active site when substrate is bound. This closed-to-open transition significantly widens the substrate-binding channel and precisely positions the scissile 1″-O-linkage for cleavage while securing tightly 2″- and 3″-hydroxyls of ADP-ribose. Our collective data uncover an unprecedented structural plasticity of ARH3 that supports its specificity for the 1″-O-linkage in substrates and Mg2+-dependent catalysis.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.RA118.003586