title: A dynamic mechanism for AKAP binding to RII isoforms of cAMP-dependent protein kinase.
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.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, San Diego, California 92093, USA.
authors.forename: Francis S
authors.initials: FS
authors.lastname: Kinderman
authors.forename: Choel
authors.initials: C
authors.lastname: Kim
authors.forename: Sventja
authors.initials: S
authors.lastname: von Daake
authors.forename: Yuliang
authors.initials: Y
authors.lastname: Ma
authors.forename: Bao Q
authors.initials: BQ
authors.lastname: Pham
authors.forename: Glen
authors.initials: G
authors.lastname: Spraggon
authors.forename: Nguyen-Huu
authors.initials: NH
authors.lastname: Xuong
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Jennings
authors.forename: Susan S
authors.initials: SS
authors.lastname: Taylor
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000378:metabolism; D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D057927:Hydrophobic and Hydrophilic Interactions; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011506:Proteins; D051381:Rats; D015398:Signal Transduction; D012996:Solutions; D013379:Substrate Specificity
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C400224:Ht 31 protein, synthetic; D007527:Isoenzymes; C517836:Prkar1a protein, rat; C517822:Prkar2a protein, rat; D011506:Proteins; D012996:Solutions; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases