The fic domain: regulation of cell signaling by adenylylation

Mol Cell. 2009 Apr 10;34(1):93-103. doi: 10.1016/j.molcel.2009.03.008.

Abstract

We show that the secreted antigen, IbpA, of the respiratory pathogen Histophilus somni induces cytotoxicity in mammalian cells via its Fic domains. Fic domains are defined by a core HPFxxGNGR motif and are conserved from bacteria to humans. We demonstrate that the Fic domains of IbpA catalyze a unique reversible adenylylation event that uses ATP to add an adenosine monophosphate (AMP) moiety to a conserved tyrosine residue in the switch I region of Rho GTPases. This modification requires the conserved histidine of the Fic core motif and renders Rho GTPases inactive. We further demonstrate that the only human protein containing a Fic domain, huntingtin yeast-interacting protein E (HYPE), also adenylylates Rho GTPases in vitro. Thus, we classify Fic domain-containing proteins as a class of enzymes that mediate bacterial pathogenesis as well as a previously unrecognized eukaryotic posttranslational modification that may regulate key signaling events.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Actin Cytoskeleton / metabolism
  • Adenosine Monophosphate / metabolism
  • Adenosine Triphosphate / metabolism
  • Amino Acid Motifs
  • Antigens, Bacterial / chemistry
  • Antigens, Bacterial / physiology*
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / physiology*
  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism
  • Carrier Proteins / physiology
  • Cysteine Endopeptidases / chemistry
  • HeLa Cells
  • Histidine / chemistry
  • Histidine / metabolism
  • Humans
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism
  • Membrane Proteins / physiology
  • Molecular Sequence Data
  • Nucleotidyltransferases
  • Pasteurellaceae / immunology*
  • Pasteurellaceae / pathogenicity
  • Phosphoric Diester Hydrolases / pharmacology
  • Sequence Alignment
  • Signal Transduction*
  • Substrate Specificity
  • Tyrosine / metabolism
  • Virulence Factors / chemistry
  • Virulence Factors / physiology*
  • rac GTP-Binding Proteins / metabolism
  • rho GTP-Binding Proteins / chemistry
  • rho GTP-Binding Proteins / metabolism

Substances

  • Antigens, Bacterial
  • Bacterial Proteins
  • Carrier Proteins
  • Membrane Proteins
  • Virulence Factors
  • YopT protein, Yersinia
  • Adenosine Monophosphate
  • Tyrosine
  • Histidine
  • Adenosine Triphosphate
  • HypE protein, human
  • Nucleotidyltransferases
  • Phosphoric Diester Hydrolases
  • Cysteine Endopeptidases
  • rac GTP-Binding Proteins
  • rho GTP-Binding Proteins