Structural Insights into the Dual Ca2+-Sensor-Mediated Activation of the PPEF Phosphatase Family

Cryo-EM reveals two structures: RDGC/apo-CaM and RDGC and Ca2+-CaM RDGC/CaM holoenzyme establishes an auto-inhibition mode in Ca2+-free condition Both CaM and EF-like/EF-hand tandem act as Ca2+-sensors to unlock the catalytic sites This dual Ca2+-sensor-mediated activation is evolutionarily conserved from Drosophila to mammals Validation of the IQ motif/CaM interaction in cryo-EM structures by higher-resolution crystal structures: mPPEF2 IQ motif (aa 22-39)/apo-CaM and RDGC IQ motif (aa 1-25)/Ca2+-CaM.