Download MendeleyEnzymatic activity with an incomplete catalytic spine - insights from a comparative structural analysis of human CK2alpha and its paralogous isoform CK2alpha'
Bischoff, N., Raaf, J., Olsen, B., Bretner, M., Issinger, O.G., Niefind, K.(2011) Mol Cell Biochem 356: 57-65
- PubMed: 21739153
- DOI: https://doi.org/10.1007/s11010-011-0948-5
- Primary Citation of Related Structures:
3RPS - PubMed Abstract:
Eukaryotic protein kinases are fundamental factors for cellular regulation and therefore subject of strict control mechanisms. For full activity a kinase molecule must be penetrated by two stacks of hydrophobic residues, the regulatory and the catalytic spine that are normally well conserved among active protein kinases. We apply this novel spine concept here on CK2α, the catalytic subunit of protein kinase CK2. Homo sapiens disposes of two paralog isoforms of CK2α (hsCK2α and hsCK2α'). We describe two new structures of hsCK2α constructs one of which in complex with the ATP-analog adenylyl imidodiphosphate and the other with the ATP-competitive inhibitor 3-(4,5,6,7-tetrabromo-1H-benzotriazol-1-yl)propan-1-ol. The former is the first hsCK2α structure with a well defined cosubstrate/magnesium complex and the second with an open β4/β5-loop. Comparisons of these structures with existing CK2α/CK2α' and cAMP-dependent protein kinase (PKA) structures reveal: in hsCK2α' an open conformation of the interdomain hinge/helix αD region that is critical for ATP-binding is found corresponding to an incomplete catalytic spine. In contrast hsCK2α often adopts the canonical, PKA-like version of the catalytic spine which correlates with a closed conformation of the hinge region. HsCK2α can switch to the incomplete, non-canonical, hsCK2α'-like state of the catalytic spine, but this transition apparently depends on binding of either ATP or of the regulatory subunit CK2β. Thus, ATP looks like an activator of hsCK2α rather than a pure cosubstrate.
Organizational Affiliation:
Universität zu Köln, Institut für Biochemie, Zülpicher Straße 47, 50674 Köln, Germany.
