Elucidating the role of the pLG72 R30K substitution in schizophrenia susceptibility.
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.
Department of Biotechnology and Life Sciences, Università degli Studi dell'Insubria, Varese, Italy.|The Protein Factory, Politecnico di Milano and Università degli Studi dell'Insubria, Italy.
Silvia
S
Sacchi
Department of Biotechnology and Life Sciences, Università degli Studi dell'Insubria, Varese, Italy.|The Protein Factory, Politecnico di Milano and Università degli Studi dell'Insubria, Italy.
Pamela
P
Cappelletti
Institute of Biostructures and Bioimaging, Italian Research National Council, Naples, Italy.
Luciano
L
Pirone
IRCCS SDN, Naples, Italy.
Giovanni
G
Smaldone
Institute of Biostructures and Bioimaging, Italian Research National Council, Naples, Italy.
Emilia
E
Pedone
Department of Biotechnology and Life Sciences, Università degli Studi dell'Insubria, Varese, Italy.|The Protein Factory, Politecnico di Milano and Università degli Studi dell'Insubria, Italy.
Loredano
L
Pollegioni
D019943:Amino Acid Substitution; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002746:Chlorpromazine / Q000737:chemistry / Q000378:metabolism; D002942:Circular Dichroism; D003605:D-Amino-Acid Oxidase / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D020125:Mutation, Missense; D011485:Protein Binding; D011487:Protein Conformation; D000072417:Protein Domains; D012559:Schizophrenia / Q000235:genetics*; D012694:Serine / Q000378:metabolism
D002352:Carrier Proteins; C475071:DAOA protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D012694:Serine; D003605:D-Amino-Acid Oxidase; D002746:Chlorpromazine
d-amino acid oxidase; d-serine; protein-protein interaction; regulation; schizophrenia