A-kinase anchoring proteins (AKAPs) target Protein Kinase A (PKA) to a variety of subcellular locations. Conventional AKAPs contain a 14-18 amino acid sequence that forms an amphipathic helix that binds with high affinity to the regulatory (R) subunit of PKA type II. More recently a group of dual-specificity AKAPs has been classified on the basis of their ability to bind the PKA type I and the PKA type II isozymes. In this report we show that dual-specificity AKAPs contain an additional PKA-binding determinant called the RI Specifier Region (RISR). A variety of protein interaction assays, immunoprecipitation and immunolocalization experiments indicate that the RISR augments RI-binding in vitro and inside cells. Cellular delivery of the RISR peptide uncouples RI anchoring to Ezrin leading to release of T cell inhibition by cAMP. Likewise, expression of mutant Ezrin forms where RI-binding has been abrogated by substitution of the RISR sequence prevents cAMP mediated inhibition of T cell function. Thus, we propose that the RISR acts in synergy with the amphipathic helix in dual-specificity anchoring proteins to enhance anchoring of PKA type I.