title: Evolutionary and structural analyses of mammalian haloacid dehalogenase-type phosphatases AUM and chronophin provide insight into the basis of their different substrate specificities.
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.
authors: From the Institute for Pharmacology and Toxicology.
authors: Annegrit
authors: A
authors: Seifried
authors: Gunnar
authors: G
authors: Knobloch
authors: Prashant S
authors: PS
authors: Duraphe
authors: Gabriela
authors: G
authors: Segerer
authors: Julia
authors: J
authors: Manhard
authors: Hermann
authors: H
authors: Schindelin
authors: Jörg
authors: J
authors: Schultz
authors: Antje
authors: A
authors: Gohla
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D006801:Humans; D008297:Male; D051379:Mice; D010749:Phosphoprotein Phosphatases / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D013379:Substrate Specificity
chemical_list: D010749:Phosphoprotein Phosphatases
keywords: Haloacid Dehalogenase Phosphatase; Molecular Evolution; Phosphatase Substrate Specificity; Phosphoglycolate Phosphatase; Pyridoxal Phosphate; Serine/Threonine Protein Phosphatase; Tyrosine-Protein Phosphatase (Tyrosine Phosphatase); X-ray Crystallography