Elucidating the role of the pLG72 R30K substitution in schizophrenia susceptibility

Silvia Sacchi, Pamela Cappelletti, Luciano Pirone, Giovanni Smaldone, Emilia Pedone, Loredano Pollegioni

Research output: Contribution to journalLetterpeer-review

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.

Original languageEnglish
Pages (from-to)646-655
Number of pages10
JournalFEBS Letters
Volume591
Issue number4
DOIs
Publication statusPublished - Feb 1 2017

Keywords

  • d-amino acid oxidase
  • d-serine
  • protein–protein interaction
  • regulation
  • schizophrenia

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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