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Evolutionary and structural analyses of mammalian haloacid dehalogenase-type phosphatases AUM and chronophin provide insight into the basis of their different substrate specificities.

Authors
  • Seifried, Annegrit1
  • Knobloch, Gunnar
  • Duraphe, Prashant S
  • Segerer, Gabriela
  • Manhard, Julia
  • Schindelin, Hermann
  • Schultz, Jörg
  • Gohla, Antje
  • 1 From the Institute for Pharmacology and Toxicology.
Type
Published Article
Journal
Journal of Biological Chemistry
Publisher
American Society for Biochemistry and Molecular Biology
Publication Date
Feb 07, 2014
Volume
289
Issue
6
Pages
3416–3431
Identifiers
DOI: 10.1074/jbc.M113.503359
PMID: 24338473
Source
Medline
Keywords
License
Unknown

Abstract

Mammalian haloacid dehalogenase (HAD)-type phosphatases are an emerging family of phosphatases with important functions in physiology and disease, yet little is known about the basis of their substrate specificity. Here, we characterize a previously unexplored HAD family member (gene annotation, phosphoglycolate phosphatase), which we termed AUM, for aspartate-based, ubiquitous, Mg(2+)-dependent phosphatase. AUM is a tyrosine-specific paralog of the serine/threonine-specific protein and pyridoxal 5'-phosphate-directed HAD phosphatase chronophin. Comparative evolutionary and biochemical analyses reveal that a single, differently conserved residue in the cap domain of either AUM or chronophin is crucial for phosphatase specificity. We have solved the x-ray crystal structure of the AUM cap fused to the catalytic core of chronophin to 2.65 Å resolution and present a detailed view of the catalytic clefts of AUM and chronophin that explains their substrate preferences. Our findings identify a small number of cap domain residues that encode the different substrate specificities of AUM and chronophin.

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