TY - JOUR
T1 - Unique utilization of a phosphoprotein phosphatase fold by a mammalian phosphodiesterase associated with WAGR syndrome
AU - Dermol, Urška
AU - Janardan, Vishnu
AU - Tyagi, Richa
AU - Visweswariah, Sandhya S.
AU - Podobnik, Marjetka
N1 - Funding Information:
We acknowledge the help of Maja Capuder and Petra Draškovič at various stages of this study. We thank the staff at the synchrotron facilities of European Molecular Biology Laboratory/Deutsches Elektronen Synchrotron (Hamburg, Germany), European Synchrotron Radiation Facility, and Elettra (beamline XRD) for support with data collection. This work was supported by the Slovenian Research Agency (M.P. and U.D.) and the Council of Scientific and Industrial Research, Government of India (S.S.V.) .
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2011/9/23
Y1 - 2011/9/23
N2 - 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.
AB - 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.
KW - AMP/GMP binding
KW - MPPED2
KW - WAGR syndrome
KW - metallophosphoesterase
KW - phosphoprotein-phosphatase-like fold
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U2 - 10.1016/j.jmb.2011.07.060
DO - 10.1016/j.jmb.2011.07.060
M3 - Article
C2 - 21824479
AN - SCOPUS:80052379416
SN - 0022-2836
VL - 412
SP - 481
EP - 494
JO - Journal of molecular biology
JF - Journal of molecular biology
IS - 3
ER -