Elucidating the role of the pLG72 R30K substitution in schizophrenia susceptibility

作者：Sacchi Silvia; Cappelletti Pamela; Pirone Luciano; Smaldone Giovanni; Pedone Emilia; Pollegioni Loredano^*

来源：FEBS LETTERS, 2017, 591(4): 646-655.

DOI：10.1002/1873-3468.12585

• D-amino acid oxidase
• D-serine
• protein-protein interaction
• regulation
• schizophrenia

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.

• 出版日期2017-2