Fig. 7

Model of the functional effect of PKCγ mutations. Normally (left panel), mature wildtype PKCγ resides in the cytosol in an autoinhibited conformation. Binding of diacylglycerol (DAG) and calcium ions (Ca²⁺) activates and promotes the translocation of PKCγ to the plasma membrane (PM), where active PKCγ phosphorylates its membrane substrates. PKCγ returns to an autoinhibited conformation (inactive) following the decay of its second messengers. The membrane-bound conformation of PKCγ is sensitive to dephosphorylation. Prolonged activation of PKCγ leads to its dephosphorylation by phosphatases. The dephosphorylated PKCγ can be tagged by ubiquitin and subsequently degraded. In contrast, in SCA14, PKCγ with mutated C1 domain adapts an open conformation and is hyper-active in the cytoplasm. (i) Highly phosphorylated mutant PKCγ forms aggregates, which accumulate in the cytoplasm due to inefficient degradation. (ii) Mutant PKCγ fails to translocation to the plasma membrane and remains in the cytoplasm. (iii) This might lead to altered phosphorylation of its substrates at the membrane and in the cytoplasm