Document Detail


Substrate-specifying determinants of the nucleotide pyrophosphatases/phosphodiesterases NPP1 and NPP2.
MedLine Citation:
PMID:  15096095     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Anisoara Cimpean; Cristiana Stefan; Rik Gijsbers; Willy Stalmans; Mathieu Bollen
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Biochemical journal     Volume:  381     ISSN:  1470-8728     ISO Abbreviation:  Biochem. J.     Publication Date:  2004 Jul 
Date Detail:
Created Date:  2004-06-21     Completed Date:  2004-11-04     Revised Date:  2011-11-07    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  England    
Other Details:
Languages:  eng     Pagination:  71-7     Citation Subset:  IM    
Affiliation:
Afdeling Biochemie, Faculteit Geneeskunde, Katholieke Universiteit Leuven, Herestraat 49, B-3000 Leuven, Belgium.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Motifs / physiology
Amino Acid Sequence / physiology
Animals
Autocrine Motility Factor / chemistry,  metabolism,  physiology*
Catalytic Domain / physiology
Glycoproteins / chemistry,  metabolism,  physiology*
Mice
Multienzyme Complexes / chemistry,  metabolism,  physiology*
Peptides / chemistry,  physiology
Phosphodiesterase I
Phosphoric Diester Hydrolases / chemistry,  metabolism,  physiology*
Protein Structure, Tertiary / physiology
Pyrophosphatases / chemistry,  metabolism,  physiology*
Rats
Recombinant Fusion Proteins / metabolism
Substrate Specificity / physiology
Threonine / physiology
Chemical
Reg. No./Substance:
0/Autocrine Motility Factor; 0/Glycoproteins; 0/Multienzyme Complexes; 0/Peptides; 0/Recombinant Fusion Proteins; 72-19-5/Threonine; EC 3.1.4.-/Phosphoric Diester Hydrolases; EC 3.1.4.1/Phosphodiesterase I; EC 3.1.4.1/ectonucleotide pyrophosphatase phosphodiesterase 1; EC 3.1.4.39/alkylglycerophosphoethanolamine phosphodiesterase; EC 3.6.1.-/Pyrophosphatases
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