structural requirements for yersinia yopj inhibition of map kinase pathways结构要求就要yopj map激酶通路的抑制.pdf

Structural Requirements for Yersinia YopJ Inhibition of MAP Kinase Pathways 1. 3. 1 1 4 2 1 Yi-Heng Hao , Yong Wang , Dara Burdette , Sohini Mukherjee , Gladys Keitany , Elizabeth Goldsmith , Kim Orth * 1 Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States of America, 2 Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States of America, 3 School of Life Science, Arizona State University, Tempe, Arizona, United States of America, 4 University of Washington School of Public Health, Seattle, Washington, United States of America 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 a-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. Citation: Hao Y-H, Wang Y, Burdette D, Mukherjee S, Keitany G, et al (2008) Structural Requirements for Yersinia YopJ Inhi