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

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 is...

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Vydáno v:	Nature communications Ročník 9; číslo 1; s. 4424 - 8
Hlavní autoři:	Kato, Kazuki, Nishimasu, Hiroshi, Oikawa, Daisuke, Hirano, Seiichi, Hirano, Hisato, Kasuya, Go, Ishitani, Ryuichiro, Tokunaga, Fuminori, Nureki, Osamu
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 24.10.2018 Nature Publishing Group Nature Portfolio
Témata:	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
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-018-06922-7