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Structure of P‐protein of the glycine cleavage system: implications for nonketotic hyperglycinemia
Author(s) -
Nakai Tadashi,
Nakagawa Noriko,
Maoka Nobuko,
Masui Ryoji,
Kuramitsu Seiki,
Kamiya Nobuo
Publication year - 2005
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600632
Subject(s) - hyperglycinemia , biology , glycine cleavage system , glycine , cleavage (geology) , biochemistry , genetics , amino acid , paleontology , fracture (geology)
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 α 2 ‐type active dimer universally observed in the evolutionarily related pyridoxal 5′‐phosphate (PLP)‐dependent enzymes. Instead, novel αβ‐type dimers associate to form an α 2 β 2 tetramer, where the α‐ and β‐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 Å. 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.