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

Srinivasan, N., Bax, B. ORCID: https://orcid.org/0000-0003-1940-3785, Blundell, T.L. and Parker, P.J. 1996. Structural aspects of the functional modules in human protein kinase-Cα deduced from comparative analyses. Proteins 26 (2) , pp. 217-235. 10.1002/(SICI)1097-0134(199610)26:2<217::AID-PROT11>3.0.CO;2-S

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Abstract

Three‐dimensional models of the five functional modules in human protein kinase Cα (PKCα) 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 kinese (cAPK) and PKI peptide. While the N‐terminal helix of the catalytic region of PKCα 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 PKCα, 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 PKCα 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. © 1996 Wiley‐Liss, Inc.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	Wiley
ISSN:	0887-3585
Last Modified:	04 Nov 2022 12:17
URI:	https://orca.cardiff.ac.uk/id/eprint/122499

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