Structure of human ADP-ribosyl-acceptor hydrolase 3 bound to ADP-ribose reveals a conformational switch that enables specific substrate recognition.
J Biol Chem
; 293(32): 12350-12359, 2018 08 10.
Article
em En
| MEDLINE
| ID: mdl-29907568
ABSTRACT
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 C1â³ 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 1â³-O-linkage for cleavage while securing tightly 2â³- and 3â³-hydroxyls of ADP-ribose. Our collective data uncover an unprecedented structural plasticity of ARH3 that supports its specificity for the 1â³-O-linkage in substrates and Mg2+-dependent catalysis.
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Base de dados:
MEDLINE
Assunto principal:
Conformação Proteica
/
Adenosina Difosfato Ribose
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Glicosídeo Hidrolases
Limite:
Humans
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2018
Tipo de documento:
Article