Schizophrenia is a chronic and severely debilitating psychiatric disorder affecting nearly 1% of the world’s population. In 2002, the new human gene G72, encoding for the pLG72 protein, and the gene encoding for DAAO have been genetically linked to the susceptibility to schizophrenia. A yeast two-hybrid screening experiment identified D-amino acid oxidase (DAAO) as a putative interacting partner of pLG72. DAAO is a FAD-containing flavooxidase that in brain is responsible for the elimination of D-serine, a co-agonist that binds to the glycine-site of the NMDA receptor. We recently demonstrated that pLG72 acts as “inactivator” of human DAAO and that the cellular concentration of D-serine depends on the expression of the active form of this flavooxidase. Based on these results, a molecular model for the onset of schizophrenia has been proposed: a decrease in pLG72 expression might yield an anomalous high level of hDAAO activity and therefore a decrease in the local concentration of D-serine, affecting glutamatergic neurotransmission mediated by NMDA receptor. The characterization of the complex is a challenging task, hardly feasible by high resolution techniques, since: 1) structural informations on pLG72 are lacking; 2) pLG72 is soluble only in the presence of mild denaturant; 3) no homologous protein has been structurally characterized so far. In this perspective, we have used low resolution strategies based on the coupling of classical biochemistry approaches (complementary proteolysis, cross-link) with mass spectrometric techniques, to characterize the pLG72-hDAAO complex. Results indicated that hDAAO exhibits different proteolysis profiles when isolated or in complex with pLG72, thus suggesting a conformational change upon binding the effector protein. Chemical cross-linking experiments will complement the proteolysis experiments providing with details the contact regions between hDAAO e pLG72.

Characterization of the human D-amino acid oxidase (hDAAO) - pLG72 complex involved in the onset of schizophrenia / G., Leo; S., Sacchi; L., Pollegioni; Birolo, Leila; Pucci, Pietro. - In: THE FEBS JOURNAL. - ISSN 1742-464X. - STAMPA. - 278:(2011), pp. 267-267. (Intervento presentato al convegno 36th FEBS Congress, Biochemistry for Tomorrow's Medicine tenutosi a Torino, Italy nel June 25-30, 2011).

Characterization of the human D-amino acid oxidase (hDAAO) - pLG72 complex involved in the onset of schizophrenia.

BIROLO, LEILA;PUCCI, PIETRO
2011

Abstract

Schizophrenia is a chronic and severely debilitating psychiatric disorder affecting nearly 1% of the world’s population. In 2002, the new human gene G72, encoding for the pLG72 protein, and the gene encoding for DAAO have been genetically linked to the susceptibility to schizophrenia. A yeast two-hybrid screening experiment identified D-amino acid oxidase (DAAO) as a putative interacting partner of pLG72. DAAO is a FAD-containing flavooxidase that in brain is responsible for the elimination of D-serine, a co-agonist that binds to the glycine-site of the NMDA receptor. We recently demonstrated that pLG72 acts as “inactivator” of human DAAO and that the cellular concentration of D-serine depends on the expression of the active form of this flavooxidase. Based on these results, a molecular model for the onset of schizophrenia has been proposed: a decrease in pLG72 expression might yield an anomalous high level of hDAAO activity and therefore a decrease in the local concentration of D-serine, affecting glutamatergic neurotransmission mediated by NMDA receptor. The characterization of the complex is a challenging task, hardly feasible by high resolution techniques, since: 1) structural informations on pLG72 are lacking; 2) pLG72 is soluble only in the presence of mild denaturant; 3) no homologous protein has been structurally characterized so far. In this perspective, we have used low resolution strategies based on the coupling of classical biochemistry approaches (complementary proteolysis, cross-link) with mass spectrometric techniques, to characterize the pLG72-hDAAO complex. Results indicated that hDAAO exhibits different proteolysis profiles when isolated or in complex with pLG72, thus suggesting a conformational change upon binding the effector protein. Chemical cross-linking experiments will complement the proteolysis experiments providing with details the contact regions between hDAAO e pLG72.
2011
Characterization of the human D-amino acid oxidase (hDAAO) - pLG72 complex involved in the onset of schizophrenia / G., Leo; S., Sacchi; L., Pollegioni; Birolo, Leila; Pucci, Pietro. - In: THE FEBS JOURNAL. - ISSN 1742-464X. - STAMPA. - 278:(2011), pp. 267-267. (Intervento presentato al convegno 36th FEBS Congress, Biochemistry for Tomorrow's Medicine tenutosi a Torino, Italy nel June 25-30, 2011).
File in questo prodotto:
File Dimensione Formato  
febs 2012 schizofrenia.pdf

accesso aperto

Tipologia: Abstract
Licenza: Dominio pubblico
Dimensione 92.13 kB
Formato Adobe PDF
92.13 kB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/449735
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? 0
social impact