Structural and biochemical insights into the activation mechanisms of germinal center kinase OSR1.

摘要: The oxidative stress-responsive 1 (OSR1) kinase belongs to the mammalian STE20-like family. OSR1 is activated by with no lysine [K] (WNKs) kinases, and then it phosphorylates cation-coupled Cl-cotransporters, regulating ion homeostasis cell volume in cells. However, specific mechanisms of activation remains poorly defined, largely due its extremely low basal activity. Here, we dissect detail regulatory from aspects autoinhibition, upstream WNK, newly identified master regulator mouse protein-25 (MO25). Based on our structural biochemical studies, propose a "double lock" model, accounting for tight autoinhibition OSR1, an effect that has be removed WNK before MO25 further activates OSR1. Particularly, conserved C-terminal (CCT) domain αAL helix act together strongly suppress WNKs bind CCT trigger conformational rearrangement release allowing binding full activation. Finally, were corroborated cellular studies OSR1-regulated control through WNK-OSR1 signaling pathway. Collectively, these results provide insights into facilitate functional study.