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The fic domain: regulation of cell signaling by adenylylation

Carolyn A Worby1, Seema Mattoo, Robert P Kruger

  • 1Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.

Molecular Cell
|April 14, 2009
PubMed

Insights

The Histophilus somni bacterium uses its IbpA protein to cause cell damage. Its Fic domains add AMP to Rho GTPases, inactivating them and revealing a new cellular modification.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Cellular Biology

Background:

  • Histophilus somni is a respiratory pathogen.
  • IbpA is a secreted antigen of H. somni.
  • Fic domains are conserved protein domains found in bacteria and eukaryotes.

Purpose of the Study:

  • To investigate the mechanism by which IbpA induces cytotoxicity.
  • To characterize the enzymatic activity of Fic domains.
  • To identify potential eukaryotic homologs and functions of Fic domains.

Main Methods:

  • Biochemical assays to study IbpA enzymatic activity.
  • Site-directed mutagenesis to identify key residues in Fic domains.
  • In vitro adenylylation assays using purified proteins.
  • Analysis of Rho GTPase activity in modified cells.

Main Results:

  • IbpA Fic domains catalyze reversible adenylylation of Rho GTPases.
  • Adenylylation occurs at a conserved tyrosine residue, inactivating Rho GTPases.
  • The conserved histidine in the Fic motif is essential for catalysis.
  • Human huntingtin yeast-interacting protein E (HYPE) also adenylylates Rho GTPases in vitro.

Conclusions:

  • Fic domain-containing proteins are involved in bacterial pathogenesis.
  • Fic domains represent a novel class of enzymes mediating posttranslational modification.
  • Adenylylation of Rho GTPases by Fic domains may regulate key cellular signaling events.

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