Unique utilization of a phosphoprotein phosphatase (PPP) fold by a mammalian phosphodiesterase associated with the WAGR syndrome

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 WAGR syndrome patients, 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. The structures of MPPED2 and two mutants are presented here, which show that the poor activity of MPPED2 is not only a consequence of substitution of an active site histidine residue by glycine, but is 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.