In the human brain, pLG72 interacts with the flavoenzyme d-amino acid oxidase (hDAAO), which is involved in catabolism of d-serine, a co-agonist of N-methyl-d-aspartate receptors (NMDAR). Here, we investigated the wild-type pLG72, the R30K variant associated with schizophrenia susceptibility, and the K62E variant. The protein conformation, oligomeric state, ligand-, and hDAAO-binding properties are only slightly modified by the substitutions. All pLG72 variants inhibit hDAAO and lead to an increase in cellular (d/d+l)-serine. However, the R30K pLG72 is significantly more prone to degradation than the R30 and the K62E variants in a cell system, thus possessing a lower ability to interact/inhibit hDAAO. This links R30K pLG72 with the hyperactivity of hDAAO, the decreased d-serine level, and NMDAR hypofunction observed in schizophrenia-affected patients.

Elucidating the role of the pLG72 R30K substitution in schizophrenia susceptibility

SACCHI, SILVIA
Primo
;
CAPPELLETTI, PAMELA;POLLEGIONI, LOREDANO
Ultimo
2017-01-01

Abstract

In the human brain, pLG72 interacts with the flavoenzyme d-amino acid oxidase (hDAAO), which is involved in catabolism of d-serine, a co-agonist of N-methyl-d-aspartate receptors (NMDAR). Here, we investigated the wild-type pLG72, the R30K variant associated with schizophrenia susceptibility, and the K62E variant. The protein conformation, oligomeric state, ligand-, and hDAAO-binding properties are only slightly modified by the substitutions. All pLG72 variants inhibit hDAAO and lead to an increase in cellular (d/d+l)-serine. However, the R30K pLG72 is significantly more prone to degradation than the R30 and the K62E variants in a cell system, thus possessing a lower ability to interact/inhibit hDAAO. This links R30K pLG72 with the hyperactivity of hDAAO, the decreased d-serine level, and NMDAR hypofunction observed in schizophrenia-affected patients.
2017
www.elsevier.com/locate/febslet
d-amino acid oxidase; d-serine; protein–protein interaction; regulation; schizophrenia; Structural Biology; Biophysics; Biochemistry; Molecular Biology; Genetics; Cell Biology
Sacchi, Silvia; Cappelletti, Pamela; Pirone, Luciano; Smaldone, Giovanni; Pedone, Emilia; Pollegioni, Loredano
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11383/2061651
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