Structure and Activation of Protein Kinase

In the absence of activating cofactors, the catalytic domain is subject to autoinhibition by the regulatory domain (Orr and Newton, 1994). A sequence motif is found in the regulatory domain which serves as a pseudosubstrate. It resembles the consensus sequence for phosphorylation sites of protein kinase C but does not have a Ser or Thr residue for phosphorylation. This sequence motif is found in aU protein kinase C family members. It is assumed that the active center is inhibited by occupation by the pseudosubstrate. 

Two functions are attributed to the binding of the activating cofactors Ca, diacyl-glycerol and phospholipid  

Detailed structural information on protein kinase C is not available at present. The reason is probably the flexibility and membrane association of protein kinase C. The first insight into the mechanism of activation was obtained by structural determination of a Cl domain (Cys2 element) of protein kinase C6 in complex with phorbol ester (Zang at al., 1995). 

From the structure of the Cys2 element with bound phorbol ester (Fig. 7.9), it was concluded that the activating function of the phorbol ester is based, in particular, in promotion of membrane association of protein kinase C. The binding site of the phor- 

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