Structural insights into cGAMP degradation by Ecto-nucleotide pyrophosphatase phosphodiesterase 1

Kazuki Kato, Hiroshi Nishimasu (), Daisuke Oikawa, Seiichi Hirano, Hisato Hirano, Go Kasuya, Ryuichiro Ishitani, Fuminori Tokunaga and Osamu Nureki ()
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Kazuki Kato: The University of Tokyo
Hiroshi Nishimasu: The University of Tokyo
Daisuke Oikawa: Osaka City University
Seiichi Hirano: The University of Tokyo
Hisato Hirano: The University of Tokyo
Go Kasuya: The University of Tokyo
Ryuichiro Ishitani: The University of Tokyo
Fuminori Tokunaga: Osaka City University
Osamu Nureki: The University of Tokyo

Nature Communications, 2018, vol. 9, issue 1, 1-8

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06922-7

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