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Role of the C2 domain in protein kinase C enzyme function

Marceen Newlon

Appointment Period: 1999-2000 / Grant Year: [15]

The goal of this project was to understand how the structure of PKC regulates its function. Specifically, this project addressed how the binding of ligands to the C1 and C2 domains results in release of the pseudosubstrate from the substrate-binding cavity. The main question to be be addressed was: what are the interfaces between the various domains of protein kinase C that allow communication between the regulatory modules and the active site? As a model system for this work, PKA was exploited due to the rich biochemistry and cell biology associated with this related kinase. This ultimately proved to be very rewarding and productive. The goal of this work was thus to understand the molecular details of how the architecture and chemistry of PKA and PKC are regulated by interactions between its domains to understand how this class of enzymes transduces cellular information.

PUBLICATIONS (resulting from this training)

Newlon MG, Roy M, Morikis D, Hausken ZE, Coghlan V, Scott JD, Jennings PA. (1999) The molecular basis for protein kinase A anchoring revealed by solution NMR. Nat Struct Biol 6:222-7.

Banky P, Newlon MG, Roy M, Garrod S, Taylor SS, Jennings PA. (2000) Isoform-specific differences between the type Ialpha and IIalpha cyclic AMP-dependent protein kinase anchoring domains revealed by solution NMR. J Biol Chem 275:35146-52.

Newlon MG, Roy M, Morikis D, Carr DW, Westphal R, Scott JD, Jennings PA. (2001) A novel mechanism of PKA anchoring revealed by solution structures of anchoring complexes. EMBO J 20:1651-62.

Morikis D, Roy M, Newlon MG, Scott JD, Jennings PA. (2002) Electrostatic properties of the structure of the docking and dimerization domain of protein kinase A IIalpha. Eur J Biochem. 269:2040-51.

Fayos R, Melacini G, Newlon MG, Burns L, Scott JD, Jennings PA. (2003) Induction of flexibility through protein-protein interactions. J Biol Chem. 278:18581-7.

Banky P, Roy M, Newlon MG, Morikis D, Haste NM, Taylor SS, Jennings PA. (2003) Related protein-protein interaction modules present drastically different surface topographies despite a conserved helical platform. J Mol Biol. 330:1117-29.