Structural insights into cGAMP degradation by Ecto-nucleotide pyrophosphatase phosphodiesterase 1.
Nat Commun
; 9(1): 4424, 2018 10 24.
Article
en En
| MEDLINE
| ID: mdl-30356045
ABSTRACT
ENPP1 (Ecto-nucleotide pyrophosphatase phosphodiesterase 1), a type II transmembrane glycoprotein, hydrolyzes ATP to produce AMP and diphosphate, thereby inhibiting bone mineralization. A recent study showed that ENPP1 also preferentially hydrolyzes 2'3'-cGAMP (cyclic GMP-AMP) but not its linkage isomer 3'3'-cGAMP, and negatively regulates the cGAS-STING pathway in the innate immune system. Here, we present the high-resolution crystal structures of ENPP1 in complex with 3'3'-cGAMP and the reaction intermediate pA(3',5')pG. The structures revealed that the adenine and guanine bases of the dinucleotides are recognized by nucleotide- and guanine-pockets, respectively. Furthermore, the structures indicate that 2'3'-cGAMP, but not 3'3'-cGAMP, binds to the active site in a conformation suitable for catalysis, thereby explaining the specific degradation of 2'3'-cGAMP by ENPP1. Our findings provide insights into how ENPP1 hydrolyzes both ATP and cGAMP to participate in the two distinct biological processes.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Pirofosfatasas
/
Hidrolasas Diéster Fosfóricas
/
Nucleótidos Cíclicos
Límite:
Humans
Idioma:
En
Revista:
Nat Commun
Asunto de la revista:
BIOLOGIA
/
CIENCIA
Año:
2018
Tipo del documento:
Article
País de afiliación:
Japón