A dynamic mechanism for AKAP binding to RII isoforms of cAMP-dependent protein kinase |
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Authors: | Kinderman Francis S Kim Choel von Daake Sventja Ma Yuliang Pham Bao Q Spraggon Glen Xuong Nguyen-Huu Jennings Patricia A Taylor Susan S |
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Institution: | Department of Chemistry and Biochemistry, University of California, San Diego, San Diego, California 92093, USA. |
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Abstract: | A kinase-anchoring proteins (AKAPs) target PKA to specific microdomains by using an amphipathic helix that docks to N-terminal dimerization and docking (D/D) domains of PKA regulatory (R) subunits. To understand specificity, we solved the crystal structure of the helical motif from D-AKAP2, a dual-specific AKAP, bound to the RIIalpha D/D domain. The 1.6 Angstrom structure reveals how this dynamic, hydrophobic docking site is assembled. A stable, hydrophobic docking groove is formed by the helical interface of two RIIalpha protomers. The flexible N terminus of one protomer is then recruited to the site, anchored to the peptide through two essential isoleucines. The other N terminus is disordered. This asymmetry provides greater possibilities for AKAP docking. Although there is strong discrimination against RIalpha in the N terminus of the AKAP helix, the hydrophobic groove discriminates against RIIalpha. RIalpha, with a cavity in the groove, can accept a bulky tryptophan, whereas RIIalpha requires valine. |
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