title: The C-terminal region of G72 increases D-amino acid oxidase activity.
abstract: The schizophrenia-related protein G72 plays a unique role in the regulation of D-amino acid oxidase (DAO) in great apes. Several psychiatric diseases, including schizophrenia and bipolar disorder, are linked to overexpression of DAO and G72. Whether G72 plays a positive or negative regulatory role in DAO activity, however, has been controversial. Exploring the molecular basis of the relationship between G72 and DAO is thus important to understand how G72 regulates DAO activity. We performed yeast two-hybrid experiments and determined enzymatic activity to identify potential sites in G72 involved in binding DAO. Our results demonstrate that residues 123-153 and 138-153 in the long isoform of G72 bind to DAO and enhance its activity by 22% and 32%, respectively. A docking exercise indicated that these G72 peptides can interact with loops in DAO that abut the entrance of the tunnel that substrate and cofactor must traverse to reach the active site. We propose that a unique gating mechanism underlies the ability of G72 to increase the activity of DAO. Because upregulation of DAO activity decreases d-serine levels, which may lead to psychiatric abnormalities, our results suggest a molecular mechanism involving interaction between DAO and the C-terminal region of G72 that can regulate N-methyl-d-aspartate receptor-mediated neurotransmission.
authors.forename: Sunny Li-Yun
authors.initials: SL
authors.lastname: Chang
authors.forename: Chia-Hung
authors.initials: CH
authors.lastname: Hsieh
authors.forename: Yen-Ju
authors.initials: YJ
authors.lastname: Chen
authors.forename: Chien-Ming
authors.initials: CM
authors.lastname: Wang
authors.forename: Chung-Shiuan
authors.initials: CS
authors.lastname: Shih
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Huang
authors.forename: Asif
authors.initials: A
authors.lastname: Mir
authors.forename: Hsien-Yuan
authors.initials: HY
authors.lastname: Lane
authors.forename: Guochuan E
authors.initials: GE
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Basic Medical Science, College of Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan. htchang@mail.cmu.edu.tw.
authors.forename: Hao-Teng
authors.initials: HT
authors.lastname: Chang
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020134:Catalytic Domain; D003605:D-Amino-Acid Oxidase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D012694:Serine / Q000378:metabolism; D020798:Two-Hybrid System Techniques
chemical_list: D002352:Carrier Proteins; C475071:DAOA protein, human; D047908:Intracellular Signaling Peptides and Proteins; D020033:Protein Isoforms; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D012694:Serine; D003605:D-Amino-Acid Oxidase