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Publication Abstract from PubMed

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.

Structural insights into cGAMP degradation by Ecto-nucleotide pyrophosphatase phosphodiesterase 1.,Kato K, Nishimasu H, Oikawa D, Hirano S, Hirano H, Kasuya G, Ishitani R, Tokunaga F, Nureki O Nat Commun. 2018 Oct 24;9(1):4424. doi: 10.1038/s41467-018-06922-7. PMID:30356045^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.