Structural aspects of the functional modules in human protein kinase-Cα deduced from comparative analyses

Abstract

Three-dimensional models of the five functional modules in human protein kinase C alpha (PKC alpha) have been generated on the basis of known related structures. The catalytic region at the C-terminus of the sequence and the N-terminal auto-inhibitory pseudo-substrate have been modeled using the crystal structure complex of cAMP-dependent protein kinase (cAPK) and PKI peptide. While the N-terminal helix of the catalytic region of PKC alpha is predicted to be in a different location compared 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 specific interactions with acidic residues in the catalytic region and may interact with the permissive phosphorylation site. Models of the two zinc-binding modules of PKC alpha are based on nuclear magnetic resonance and crystal structures of such modules in other PKC isoforms while the calcium phospholipid binding module (C2) is based on the crystal structure 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 experiments.

Biography of a scientist with strength, substance, sincerity and service: Late N. Srinivasan (1962-2021)

“…NS also interacted with colleagues who worked on wet-lab biology and signal transduction. Indeed, some of his papers on pentraxin [ 6 ], PH domains [ 7 ], kinases [ 8 - 9 ] and protein symmetry [ 10 ] are noteworthy. He also learnt the collaborative skills by discussions with other labs in Birkbeck College, as opportunities were provided generously by TLB [ 11 ].…”

Srinivasan (1962–2021) in Bioinformatics and beyond

“…During these times, his research was largely focused on homology modelling ( Johnson et al , 1994 ) and the study of proteins involved in signal transduction (e.g. Srinivasan et al , 1994 , 1996 ). After coming back to MBU, he headed the ‘Proteins: structure, function and evolutionary’ group.…”