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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Actin Cytoskeleton / metabolism
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Adenosine Monophosphate / metabolism
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Adenosine Triphosphate / metabolism
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Amino Acid Motifs
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Antigens, Bacterial / chemistry
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Antigens, Bacterial / physiology*
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Bacterial Proteins / chemistry
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Bacterial Proteins / physiology*
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Carrier Proteins / chemistry
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Carrier Proteins / metabolism
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Carrier Proteins / physiology
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Cysteine Endopeptidases / chemistry
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HeLa Cells
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Histidine / chemistry
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Histidine / metabolism
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Humans
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Membrane Proteins / chemistry
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Membrane Proteins / metabolism
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Membrane Proteins / physiology
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Molecular Sequence Data
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Nucleotidyltransferases
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Pasteurellaceae / immunology*
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Pasteurellaceae / pathogenicity
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Phosphoric Diester Hydrolases / pharmacology
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Sequence Alignment
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Signal Transduction*
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Substrate Specificity
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Tyrosine / metabolism
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Virulence Factors / chemistry
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Virulence Factors / physiology*
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rac GTP-Binding Proteins / metabolism
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rho GTP-Binding Proteins / chemistry
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rho GTP-Binding Proteins / metabolism
Substances
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Antigens, Bacterial
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Bacterial Proteins
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Carrier Proteins
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Membrane Proteins
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Virulence Factors
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YopT protein, Yersinia
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Adenosine Monophosphate
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Tyrosine
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Histidine
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Adenosine Triphosphate
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FICD protein, human
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Nucleotidyltransferases
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Phosphoric Diester Hydrolases
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Cysteine Endopeptidases
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rac GTP-Binding Proteins
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rho GTP-Binding Proteins