VopA inhibits ATP binding by acetylating the catalytic loop of MAPK kinases.
The bacterial pathogen Vibrio parahemeolyticus manipulates host signaling pathways during infections by injecting type III effectors. One of these effectors, Vibrio outer protein A (VopA), inhibits MAPK signaling via a novel mechanism, distinct from those described for other bacterial toxins, that disrupts this signaling pathway. VopA is an acetyltransferase that potently inhibits MAPK signaling pathways not only by preventing the activation of MAPK kinases (MKKs) but also by inhibiting the activity of activated MKKs. VopA acetylates a conserved lysine found in the catalytic loop of all kinases and blocks the binding of ATP, but not ADP, on the MKKs, resulting in an inactive phosphorylated kinase. Acetylation of this conserved lysine inhibits kinase activity by a new mechanism of regulation that has not been observed previously. Identifying the target of VopA reveals a way that the reversible post-translational modification of lysine acetylation can be used to regulate the activity of an enzyme.
Trosky
Jennifer E
JE
Department of Molecular Biology, Protein Chemistry Technology Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Li
Yan
Y
Mukherjee
Sohini
S
Keitany
Gladys
G
Ball
Haydn
H
Orth
Kim
K
D000107:Acetylation / Q000187:drug effects; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D051046:Amino-Acid N-Acetyltransferase / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism* / Q000494:pharmacology; D001427:Bacterial Toxins / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D008239:Lysine / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D014735:Vibrio Infections / Q000201:enzymology*; D014736:Vibrio parahaemolyticus / Q000201:enzymology* / Q000472:pathogenicity
D001425:Bacterial Outer Membrane Proteins; D001427:Bacterial Toxins; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D051046:Amino-Acid N-Acetyltransferase; D020929:Mitogen-Activated Protein Kinase Kinases; D008239:Lysine