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

• Published in: Nature communications 2018-10, Vol.9 (1), p.4424-8, Article 4424
• Main Authors: Kato, Kazuki, Nishimasu, Hiroshi, Oikawa, Daisuke, Hirano, Seiichi, Hirano, Hisato, Kasuya, Go, Ishitani, Ryuichiro, Tokunaga, Fuminori, Nureki, Osamu
• Format: Article
• Language: English
• Subjects: 13/95; 631/337; 631/45/173; 631/535/1266; Adenine; Adenosine; Adenosine triphosphate; Adenosine Triphosphate - metabolism; AMP; Biological activity; Catalysis; Cell Line; Cell Line, Tumor; Conformation; Crystal structure; Crystallization; Cyclic GMP; Degradation; Glycoproteins; Guanine; HEK293 Cells; Humanities and Social Sciences; Humans; Hydrogen bonds; Immune system; Innate immunity; Membrane Proteins - metabolism; Mineralization; multidisciplinary; Nucleotides, Cyclic - chemistry; Nucleotides, Cyclic - metabolism; Phosphodiesterase; Phosphoric Diester Hydrolases - chemistry; Phosphoric Diester Hydrolases - metabolism; Protein Structure, Secondary; Pyrophosphatase; Pyrophosphatases - chemistry; Pyrophosphatases - metabolism; Reaction intermediates; Science; Science (multidisciplinary); Signal Transduction - physiology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-06922-7

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. Ecto-nucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) is a type II transmembrane glycoprotein that hydrolyzes both ATP and cGAMP. Here the authors present the crystal structures of the extracellular domain of mouse ENPP1 in complex with 3′3′-cGAMP and the reaction intermediate pA(3′,5′)pG and discuss mechanistic implications.