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A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α
Published on: November 2, 2018
PKA type IIalpha holoenzyme reveals a combinatorial strategy for isoform diversity
Jian Wu1, Simon H J Brown, Sventja von Daake
1Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
Science (New York, N.Y.)
|October 13, 2007
Summary
Cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) regulatory subunits RI and RII exhibit distinct structures and functions. The RIIalpha holoenzyme structure reveals key conformational changes important for PKA regulation.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Biology
Background:
- Cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) is regulated by RI and RII subunits.
- RII subunits act as substrates and inhibitors, differing from RI subunits in adenosine triphosphate (ATP) independence for holoenzyme formation.
Purpose of the Study:
- To elucidate the molecular basis of isoform diversity between RI and RII regulatory subunits of PKA.
- To compare the crystal structure of RIIalpha holoenzyme with the previously determined RIalpha holoenzyme.
Main Methods:
- X-ray crystallography was used to solve the crystal structure of an RIIalpha holoenzyme.
- Comparative structural analysis was performed between RIIalpha and RIalpha holoenzymes.
Main Results:
- The RIIalpha holoenzyme structure reveals significant conformational changes, including the wrapping of cAMP-binding domains around the catalytic (C) subunit.
- A key conformational reorganization involves a helix switch in domain A of the RIIalpha subunit.
- The C subunit adopts an open conformation, with a disordered carboxyl-terminal tail in the RIIalpha holoenzyme.
Conclusions:
- The study highlights conserved and isoform-specific features of RI and RII subunits.
- The findings underscore the role of ATP in PKA regulation and provide insights into designing isoform-specific PKA modulators.
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