Crystal structure of the human, FIC-domain containing protein HYPE and implications for its functions

  • Structure. 2014 Dec 2;22(12):1831-1843. doi: 10.1016/j.str.2014.10.007.
Tom D Bunney  1 ,  Ambrose R Cole  2 ,  Malgorzata Broncel  3 ,  Diego Esposito  4 ,  Edward W Tate  3 ,  Matilda Katan  5
Affiliations
  • 1. Division of Biosciences, Institute of Structural and Molecular Biology, University College London, Gower Street, London WC1E 6BT, UK. Electronic address: [email protected].
  • 2. Institute of Structural and Molecular Biology, Birkbeck College, London WC1 7HX, UK.
  • 3. Department of Chemistry, Imperial College London, South Kensington Campus, Exhibition Road, London SW7 2AZ, UK.
  • 4. Division of Molecular Structure, MRC-National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
  • 5. Division of Biosciences, Institute of Structural and Molecular Biology, University College London, Gower Street, London WC1E 6BT, UK. Electronic address: [email protected].
PMID: 25435325 DOI: 10.1016/j.str.2014.10.007
Abstract

Protein AMPylation, the transfer of AMP from ATP to protein targets, has been recognized as a new mechanism of host-cell disruption by some Bacterial effectors that typically contain a FIC-domain. Eukaryotic genomes also encode one FIC-domain protein,HYPE, which has remained poorly characterized.Here we describe the structure of human HYPE, solved by X-ray crystallography, representing the first structure of a eukaryotic FIC-domain protein. We demonstrate that HYPE forms stable dimers with structurally and functionally integrated FIC-domains and with TPR-motifs exposed for protein-protein interactions. As HYPE also uniquely possesses a transmembrane helix, dimerization is likely to affect its positioning and function in the membrane vicinity. The low rate of auto AMPylation of the wild-type HYPE could be due to autoinhibition, consistent with the mechanism proposed for a number of putative FIC AMPylators. Our findings also provide a basis to further consider possible alternative cofactors of HYPE and distinct modes of target-recognition.