Title
Elucidating the role of the pLG72 R30K substitution in schizophrenia susceptibility
Author
Silvia Sacchi, Pamela Cappelletti, Luciano Pirone, Giovanni Smaldone, Emilia Pedone, Loredano Pollegioni
Year
2017
Journal
FEBS Letters
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. 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.
Instrument
J-810
Keywords
Circular dichroism, Secondary structure, Tertiary structure, Thermal stability, Thermodynamics, Biochemistry