STRUCTURAL ASPECTS OF THE FUNCTIONAL MODULES IN HUMAN PROTEIN KINASE-C-ALPHA DEDUCED FROM COMPARATIVE ANALYSES

Three-dimensional models of the five functional modules in human prote in kinase C alpha (PKC alpha) have been generated on the basis of know n related structures, The catalytic region at the C-terminus of the se quence and the N-terminal auto-inhibitory pseudo-substrate have been m odeled using the crystal structure complex of cAMP-dependent protein k inase (cAPK) and PKI peptide, While the N-terminal helix of the cataly tic region of PKC alpha is predicted to be in a different location com pared with cAPK, the C-terminal extension is modeled like that in the cAPK. The predicted permissive phosphorylation site of PKC alpha, Thr 497, is found to be entirely consistent with the mutagenesis studies, Basic Lys and Arg residues in the pseudo-substrate make several specif ic interactions with acidic residues in the catalytic region and may i nteract with the permissive phosphorylation site, Models of the two zi nc-binding modules of PKC alpha are based on nuclear magnetic resonanc e and crystal structures of such modules in other PKC isoforms while t he calcium phospholipid binding module (C2) is based on the crystal st ructure of a repeating unit in synaptotagmin I. Phorbol ester binding regions in zinc-binding modules and the calcium binding region in the C2 domain are similar to those in the basis structures. A hypothetical model of the relative positions of all five modules has the putative lipid binding ends of the C2 and the two zinc-binding domains pointing in the same direction and may serve as a basis for further experiment s. (C) 1996 Wiley-Liss, Inc.