Substrate-specifying determinants of the nucleotide pyrophosphatases/phosphodiesterases NPP1 and NPP2

The nucleotide pyrophosphatases/phosphodiesterases NPP1 and NPP2/autotaxin are structurally related eukaryotic ecto-enzymes, but display a very different substrate specificity. NPP1 releases nucleoside 5′-monophosphates from various nucleotides, whereas NPP2 mainly functions as a lysophospholipase D...

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Main Authors: Cimpean, Anisoara, Stefan, Cristiana, Gijsbers, Rik, Stalmans, Willy, Bollen, Mathieu
Formato: Artigo
Idioma:English
Publicado em: Portland Press Ltd. 2004
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Research Article
Acesso em linha:https://ncbi.nlm.nih.gov/pmc/articles/PMC1133763/
https://ncbi.nlm.nih.gov/pubmed/15096095
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1042/BJ20040465
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spelling pubmed-11337632005-09-07 Substrate-specifying determinants of the nucleotide pyrophosphatases/phosphodiesterases NPP1 and NPP2 Cimpean, Anisoara Stefan, Cristiana Gijsbers, Rik Stalmans, Willy Bollen, Mathieu Biochem J Research Article The nucleotide pyrophosphatases/phosphodiesterases NPP1 and NPP2/autotaxin are structurally related eukaryotic ecto-enzymes, but display a very different substrate specificity. NPP1 releases nucleoside 5′-monophosphates from various nucleotides, whereas NPP2 mainly functions as a lysophospholipase D. We have used a domain-swapping approach to map substrate-specifying determinants of NPP1 and NPP2. The catalytic domain of NPP1 fused to the N- and C-terminal domains of NPP2 was hyperactive as a nucleotide phosphodiesterase, but did not show any lysophospholipase D activity. In contrast, chimaeras of the catalytic domain of NPP2 and the N- and/or C-terminal domains of NPP1 were completely inactive. These data indicate that the catalytic domain as well as both extremities of NPP2 contain lysophospholipid-specifying sequences. Within the catalytic domain of NPP1 and NPP2, we have mapped residues close to the catalytic site that determine the activities towards nucleotides and lysophospholipids. We also show that the conserved Gly/Phe-Xaa-Gly-Xaa-Xaa-Gly (G/FXGXXG) motif near the catalytic site is required for metal binding, but is not involved in substrate-specification. Our data suggest that the distinct activities of NPP1 and NPP2 stem from multiple differences throughout the polypeptide chain. Portland Press Ltd. 2004-06-22 2004-07-01 /pmc/articles/PMC1133763/ /pubmed/15096095 http://dx.doi.org/10.1042/BJ20040465 Text en The Biochemical Society, London
institution US National Library of Medicine
collection PubMed Central
language English
format Article
topic Research Article
spellingShingle Research Article
Cimpean, Anisoara
Stefan, Cristiana
Gijsbers, Rik
Stalmans, Willy
Bollen, Mathieu
Substrate-specifying determinants of the nucleotide pyrophosphatases/phosphodiesterases NPP1 and NPP2
description The nucleotide pyrophosphatases/phosphodiesterases NPP1 and NPP2/autotaxin are structurally related eukaryotic ecto-enzymes, but display a very different substrate specificity. NPP1 releases nucleoside 5′-monophosphates from various nucleotides, whereas NPP2 mainly functions as a lysophospholipase D. We have used a domain-swapping approach to map substrate-specifying determinants of NPP1 and NPP2. The catalytic domain of NPP1 fused to the N- and C-terminal domains of NPP2 was hyperactive as a nucleotide phosphodiesterase, but did not show any lysophospholipase D activity. In contrast, chimaeras of the catalytic domain of NPP2 and the N- and/or C-terminal domains of NPP1 were completely inactive. These data indicate that the catalytic domain as well as both extremities of NPP2 contain lysophospholipid-specifying sequences. Within the catalytic domain of NPP1 and NPP2, we have mapped residues close to the catalytic site that determine the activities towards nucleotides and lysophospholipids. We also show that the conserved Gly/Phe-Xaa-Gly-Xaa-Xaa-Gly (G/FXGXXG) motif near the catalytic site is required for metal binding, but is not involved in substrate-specification. Our data suggest that the distinct activities of NPP1 and NPP2 stem from multiple differences throughout the polypeptide chain.
author Cimpean, Anisoara
Stefan, Cristiana
Gijsbers, Rik
Stalmans, Willy
Bollen, Mathieu
author_facet Cimpean, Anisoara
Stefan, Cristiana
Gijsbers, Rik
Stalmans, Willy
Bollen, Mathieu
author_sort Cimpean, Anisoara
title Substrate-specifying determinants of the nucleotide pyrophosphatases/phosphodiesterases NPP1 and NPP2
title_short Substrate-specifying determinants of the nucleotide pyrophosphatases/phosphodiesterases NPP1 and NPP2
title_full Substrate-specifying determinants of the nucleotide pyrophosphatases/phosphodiesterases NPP1 and NPP2
title_fullStr Substrate-specifying determinants of the nucleotide pyrophosphatases/phosphodiesterases NPP1 and NPP2
title_full_unstemmed Substrate-specifying determinants of the nucleotide pyrophosphatases/phosphodiesterases NPP1 and NPP2
title_sort substrate-specifying determinants of the nucleotide pyrophosphatases/phosphodiesterases npp1 and npp2
publisher Portland Press Ltd.
publisher_facet Portland Press Ltd.
publishDate 2004
url https://ncbi.nlm.nih.gov/pmc/articles/PMC1133763/
https://ncbi.nlm.nih.gov/pubmed/15096095
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1042/BJ20040465
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