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BMC Pharmacology

, 9:P6 | Cite as

The first crystal structure of cyclic GMP-dependent protein kinase Iβ dimerization/docking domain reveals molecular details of isoform-specific anchoring

  • Darren E Casteel
  • Eric V Smith-Nguyen
  • Banumathi Sankaran
  • Glen Spraggon
  • Eric N Hampton
  • Renate B Pilz
  • Susan S Taylor
  • Choel Kim
Open Access
Poster presentation
  • 1.6k Downloads

Keywords

Salt Bridge Destabilize Effect Multiprotein Complex Molecular Detail Anchor Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Background

Cyclic GMP-dependent protein kinase (PKG) is the main mediator of the NO/cGMP signaling pathway and plays a central role in regulating cardiovascular and neuronal functions. Subcellular targeting of PKG provides a mechanism for achieving substrate specificity and is mediated by the most N-terminal ~50 amino acids, which are required for homo-dimerization of the kinase and association with isoform-specific G-k inase a nchoring p roteins (GKAPs). To understand the molecular details of PKG dimerization and targeting to GKAPs, we solved a crystal structure of the PKG Iβ dimerization/docking domain.

Results

The structure reveals two helices wrapping around each other into a left-handed helix and forming a parallel coiled-coil. Two unusual interhelical salt bridges stabilize the coiled-coil, as confirmed by the destabilizing effects of single alanine substitutions. The two interhelical ion pairs flank a patch of acidic residues that are crucial for GKAP binding. This is the first crystal structure available for PKG; it demonstrates not only the molecular details of PKG Iβ dimerization, but also reveal the docking surface for GKAPs.

It is increasingly evident that the fidelity of signal transduction is dependent on the ability of proteins to assemble into pathway specific multiprotein complexes. We also showed that the surrogate domain of the closely related cAMP-dependent protein kinase (PKA) forms an X-type helical bundle (Figure 1), providing a completely different docking surface for binding PKA specific anchoring proteins [1]. The coiled-coil is also a highly important model system for studying fundamental principles in protein folding, stability and specificity.
Figure 1

Structures of the Dimerization/Docking domains.

References

  1. 1.
    Kinderman FS, Kim C, von Daake S, Ma Y, Pham BQ, Spraggon G, Xuong NH, Jennings PA, Taylor SS: A dynamic mechanism for AKAP binding to RII isoforms of cAMP-dependent protein kinase. Mol Cell. 2006, 24: 397-408. 10.1016/j.molcel.2006.09.015.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Casteel et al; licensee BioMed Central Ltd. 2009

This article is published under license to BioMed Central Ltd.

Authors and Affiliations

  • Darren E Casteel
    • 1
  • Eric V Smith-Nguyen
    • 2
  • Banumathi Sankaran
    • 3
  • Glen Spraggon
    • 4
  • Eric N Hampton
    • 4
  • Renate B Pilz
    • 1
  • Susan S Taylor
    • 2
    • 5
    • 6
  • Choel Kim
    • 7
  1. 1.Department of Medicine and Cancer CenterUniversity of CaliforniaSan DiegoUSA
  2. 2.Department of Chemistry and BiochemistryUniversity of CaliforniaSan DiegoUSA
  3. 3.The Berkeley Center for Structural BiologyLawrence Berkeley National LaboratoryBerkeleyUSA
  4. 4.Genomics Institute of the Novartis Research FoundationSan DiegoUSA
  5. 5.Howard Hughes Medical InstituteUniversity of CaliforniaSan DiegoUSA
  6. 6.Department of PharmacologyUniversity of CaliforniaSan DiegoUSA
  7. 7.Department of PharmacologyBaylor College of MedicineHoustonUSA

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