Unique Utilization of a Phosphoprotein Phosphatase Fold by a Mammalian Phosphodiesterase Associated With WAGR Syndrome

J Mol Biol. 2011 Sep 23;412(3):481-94. doi: 10.1016/j.jmb.2011.07.060. Epub 2011 Jul 30.

Abstract

Metallophosphoesterase-domain-containing protein 2 (MPPED2) is a highly evolutionarily conserved protein with orthologs found from worms to humans. The human MPPED2 gene is found in a region of chromosome 11 that is deleted in patients with WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) syndrome, and MPPED2 may function as a tumor suppressor. However, the precise cellular roles of MPPED2 are unknown, and its low phosphodiesterase activity suggests that substrate hydrolysis may not be its prime function. We present here the structures of MPPED2 and two mutants, which show that the poor activity of MPPED2 is not only a consequence of the substitution of an active-site histidine residue by glycine but also due to binding of AMP or GMP to the active site. This feature, enhanced by structural elements of the protein, allows MPPED2 to utilize the conserved phosphoprotein-phosphatase-like fold in a unique manner, ensuring that its enzymatic activity can be combined with a possible role as a scaffolding or adaptor protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Monophosphate / metabolism
  • Amino Acid Sequence
  • Amino Acid Substitution / genetics
  • Catalytic Domain
  • Crystallography, X-Ray
  • Guanosine Monophosphate / metabolism
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Mutant Proteins / chemistry
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Phosphoric Diester Hydrolases / chemistry*
  • Phosphoric Diester Hydrolases / genetics
  • Phosphoric Diester Hydrolases / metabolism*
  • Protein Binding
  • Protein Structure, Tertiary
  • Sequence Alignment
  • Sequence Homology, Amino Acid

Substances

  • Mutant Proteins
  • Adenosine Monophosphate
  • Guanosine Monophosphate
  • MPPED2 protein, human
  • Phosphoric Diester Hydrolases

Associated data

  • PDB/3RL3
  • PDB/3RL4
  • PDB/3RL5