title: Structure of P-protein of the glycine cleavage system: implications for nonketotic hyperglycinemia.
abstract: The crystal structure of the P-protein of the glycine cleavage system from Thermus thermophilus HB8 has been determined. This is the first reported crystal structure of a P-protein, and it reveals that P-proteins do not involve the alpha(2)-type active dimer universally observed in the evolutionarily related pyridoxal 5'-phosphate (PLP)-dependent enzymes. Instead, novel alphabeta-type dimers associate to form an alpha(2)beta(2) tetramer, where the alpha- and beta-subunits are structurally similar and appear to have arisen by gene duplication and subsequent divergence with a loss of one active site. The binding of PLP to the apoenzyme induces large open-closed conformational changes, with residues moving up to 13.5 A. The structure of the complex formed by the holoenzyme bound to an inhibitor, (aminooxy)acetate, suggests residues that may be responsible for substrate recognition. The molecular surface around the lipoamide-binding channel shows conservation of positively charged residues, which are possibly involved in complex formation with the H-protein. These results provide insights into the molecular basis of nonketotic hyperglycinemia.
authors.affiliation: RIKEN Harima Institute at SPring-8, Mikazuki, Sayo, Hyogo, Japan. nakaix@spring8.or.jp
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakai
authors.forename: Noriko
authors.initials: N
authors.lastname: Nakagawa
authors.forename: Nobuko
authors.initials: N
authors.lastname: Maoka
authors.forename: Ryoji
authors.initials: R
authors.lastname: Masui
authors.forename: Seiki
authors.initials: S
authors.lastname: Kuramitsu
authors.forename: Nobuo
authors.initials: N
authors.lastname: Kamiya
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D050961:Glycine Decarboxylase Complex H-Protein; D050841:Glycine Dehydrogenase (Decarboxylating); D006801:Humans; D020158:Hyperglycinemia, Nonketotic / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D016963:Thermus thermophilus / Q000737:chemistry / Q000378:metabolism; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D050961:Glycine Decarboxylase Complex H-Protein; D021122:Protein Subunits; D008063:Thioctic Acid; C013091:lipoamide; D000594:Amino Acid Oxidoreductases; D050841:Glycine Dehydrogenase (Decarboxylating)