C Subunits Binding to the Protein Kinase A RIα Dimer Induce a Large Conformational Change

William T. Heller, Dominico Vigil, Simon Brown, Donald K. Blumenthal, Susan S. Taylor, Jill Trewhella

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

We present structural data on the RIα isoform of the cAMP-dependent protein kinase A that reveal, for the first time, a large scale conformational change within the RIα homodimer upon catalytic subunit binding. This result infers that the inhibition of catalytic subunit activity is not the result of a simple docking process but rather is a multi-step process involving local conformational changes both in the cAMP-binding domains as well as in the linker region of the regulatory subunit that impact the global structure of the regulatory homodimer. The results were obtained using small-angle neutron scattering with contrast variation and deuterium labeling. From these experiments we derived information on the shapes and dispositions of the catalytic subunits and regulatory homodimer within a holoenzyme reconstituted with a deuterated regulatory subunit. The scattering data also show that, despite extensive sequence homology between the isoforms, the overall structure of the type Iα holoenzyme is significantly more compact than the type Ha isoform. We present a model of the type Iα holoenzyme, built using available high-resolution structures of the component subunits and domains, which best fits the neutron-scattering data. In this model, the type Iα holoenzyme forms a flattened V shape with the RIα dimerization domain at the point of the V and the cAMP-binding domains of the RIα subunits with their bound catalytic subunits at the ends.

Original languageEnglish
Pages (from-to)19084-19090
Number of pages7
JournalJournal of Biological Chemistry
Volume279
Issue number18
DOIs
StatePublished - Apr 30 2004

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