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PMID:17244817

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Citation

Rodriguez de la Vega, M, Sevilla, RG, Hermoso, A, Lorenzo, J, Tanco, S, Diez, A, Fricker, LD, Bautista, JM and Avilés, FX (2007) Nna1-like proteins are active metallocarboxypeptidases of a new and diverse M14 subfamily. FASEB J. 21:851-65

Abstract

Nna1 has some sequence similarity to metallocarboxypeptidases, but the biochemical characterization of Nna1 has not previously been reported. In this work we performed a detailed genomic scan and found >100 Nna1 homologues in bacteria, Protista, and Animalia, including several paralogs in most eukaryotic species. Phylogenetic analysis of the Nna1-like sequences demonstrates a major divergence between Nna1-like peptidases and the previously known metallocarboxypeptidases subfamilies: M14A, M14B, and M14C. Conformational modeling of representative Nna1-like proteins from a variety of species indicates an unusually open active site, a property that might facilitate its action on a wide variety of peptide and protein substrates. To test this, we expressed a recombinant form of one of the Nna1-like peptidases from Caenorhabditis elegans and demonstrated that this protein is a fully functional metallocarboxypeptidase that cleaves a range of C-terminal amino acids from synthetic peptides. The enzymatic activity is activated by ATP/ADP and salt-inactivated, and is preferentially inhibited by Z-Glu-Tyr dipeptide, which is without precedent in metallocarboxypeptidases and resembles tubulin carboxypeptidase functioning; this hypothesis is strongly reinforced by the results depicted in Kalinina et al. published as accompanying paper in this journal. Our findings demonstrate that the M14 family of metallocarboxypeptidases is more complex and diverse than expected, and that Nna1-like peptidases are functional variants of such enzymes, representing a novel subfamily (we propose the name M14D) that contributes substantially to such diversity.

Links

PubMed Online version:10.1096/fj.06-7330com

Keywords

Animals; Bacteria/enzymology; Bacteria/genetics; Base Sequence; Binding Sites; Carboxypeptidases/chemistry; Carboxypeptidases/genetics; Carboxypeptidases/metabolism; GTP-Binding Proteins/chemistry; GTP-Binding Proteins/genetics; Mice; Molecular Sequence Data; Peptide Hydrolases/classification; Peptide Hydrolases/metabolism; Protein Conformation; Protein Structure, Tertiary; Sequence Homology, Amino Acid; Serine-Type D-Ala-D-Ala Carboxypeptidase/chemistry; Serine-Type D-Ala-D-Ala Carboxypeptidase/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

CAEEL:CBPC6

enables

GO:0004181: metallocarboxypeptidase activity

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

CAEEL:CBPC6

involved_in

GO:0006508: proteolysis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:CBPC6

enables

GO:0004181: metallocarboxypeptidase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:CBPC3

enables

GO:0004181: metallocarboxypeptidase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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