pLG72 modulates intracellular D-serine levels through its interaction with D-amino acid oxidase: effect on schizophrenia susceptibility.
J. Biol. Chem.. 2008-06-10; 283(32): 22244-22256
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1. J Biol Chem. 2008 Aug 8;283(32):22244-56. doi: 10.1074/jbc.M709153200. Epub 2008
pLG72 modulates intracellular D-serine levels through its interaction with
D-amino acid oxidase: effect on schizophrenia susceptibility.
Sacchi S(1), Bernasconi M, Martineau M, Mothet JP, Ruzzene M, Pilone MS,
Pollegioni L, Molla G.
(1)Department of Biotechnology and Molecular Sciences, University of Insubria,
Via J. H. Dunant, 3, 21100 Varese, Italy.
Human genes coding for pLG72 and d-amino acid oxidase have recently been linked
to the onset of schizophrenia. pLG72 was proposed as an activator of the human
FAD-containing flavoprotein d-amino acid oxidase (hDAAO). In the brain this
oxidizes d-serine, a potent activator of N-methyl-d-aspartate receptor. We have
investigated the mechanistic regulation of hDAAO by pLG72. Immunohistochemical
analyses revealed that hDAAO and pLG72 are both expressed in astrocytes of the
human cortex, where they most likely interact, considering their partial
overlapping subcellular distribution and their coimmunoprecipitation. We
demonstrated that the specific in vitro interaction of the two proteins yields a
complex composed of 2 hDAAO homodimers and 2 pLG72 molecules. Binding of pLG72
did not affect the kinetic properties and FAD binding ability of hDAAO; instead,
a time-dependent loss of hDAAO activity in the presence of an excess of pLG72 was
found. The binding affects the tertiary structure of hDAAO, altering the amount
of the active form. We finally demonstrated that overexpression of hDAAO in
glioblastoma cells decreases the levels of d-serine, an effect that is null when
pLG72 is coexpressed. These data indicate that pLG72 acts as a negative effector
of hDAAO. Therefore, a decrease in the synaptic concentration of d-serine as the
result of an anomalous increase in hDAAO activity related to hypoexpression of
pLG72 may represent a molecular mechanism by which hDAAO and pLG72 are involved
in schizophrenia susceptibility.
PMID: 18544534 [Indexed for MEDLINE]