Structural requirements for Yersinia YopJ inhibition of MAP kinase pathways.
MAPK signaling cascades are evolutionally conserved. The bacterial effector, YopJ, uses the unique activity of Ser/Thr acetylation to inhibit the activation of the MAPK kinase (MKK) and prevent activation by phosphorylation. YopJ is also able to block yeast MAPK signaling pathways using this mechanism. Based on these observations, we performed a genetic screen to isolate mutants in the yeast MKK, Pbs2, that suppress YopJ inhibition. One suppressor contains a mutation in a conserved tyrosine residue and bypasses YopJ inhibition by increasing the basal activity of Pbs2. Mutations on the hydrophobic face of the conserved G alpha-helix in the kinase domain prevent both binding and acetylation by YopJ. Corresponding mutants in human MKKs showed that they are conserved not only structurally, but also functionally. These studies reveal a conserved binding site found on the superfamily of MAPK kinases while providing insight into the molecular interactions required for YopJ inhibition.
Hao
Yi-Heng
YH
Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
Wang
Yong
Y
Burdette
Dara
D
Mukherjee
Sohini
S
Keitany
Gladys
G
Goldsmith
Elizabeth
E
Orth
Kim
K
D000107:Acetylation; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015010:Yersinia pestis / Q000502:physiology
D001426:Bacterial Proteins; D029701:Saccharomyces cerevisiae Proteins; C109227:YopP protein, Yersinia; D020929:Mitogen-Activated Protein Kinase Kinases; C089356:PBS2 protein, S cerevisiae