Structure of P‐protein of the glycine cleavage system: implications for nonketotic hyperglycinemia

Structure of P‐protein of the glycine cleavage system: implications for nonketotic hyperglycinemia 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 α2‐type active dimer universally observed in the evolutionarily related pyridoxal 5′‐phosphate (PLP)‐dependent enzymes. Instead, novel αβ‐type dimers associate to form an α2β2 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The EMBO Journal Wiley

Structure of P‐protein of the glycine cleavage system: implications for nonketotic hyperglycinemia

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Publisher
Wiley
Copyright
Copyright © 2013 Wiley Periodicals, Inc
ISSN
0261-4189
eISSN
1460-2075
DOI
10.1038/sj.emboj.7600632
Publisher site
See Article on Publisher Site

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 α2‐type active dimer universally observed in the evolutionarily related pyridoxal 5′‐phosphate (PLP)‐dependent enzymes. Instead, novel αβ‐type dimers associate to form an α2β2 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.

Journal

The EMBO JournalWiley

Published: Aug 20, 2006

Keywords: ; ; ; ;

References

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