D-AKAP2:PKA RII:PDZK1 ternary complex structure: Insights from the nucleation of a polyvalent scaffold

Ganapathy N. Sarma, Issa S. Moody, Ronit Ilouz, Ryan H. Phan, Banumathi Sankaran, Randy A. Hall, Susan S. Taylor

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


A-kinase anchoring proteins (AKAPs) regulate cAMP-dependent protein kinase (PKA) signaling in space and time. Dual-specific AKAP2 (D-AKAP2/AKAP10) binds with high affinity to both RI and RII regulatory subunits of PKA and is anchored to transporters through PDZ domain proteins. Here, we describe a structure of D-AKAP2 in complex with two interacting partners and the exact mechanism by which a segment that on its own is disordered presents an α-helix to PKA and a β-strand to PDZK1. These two motifs nucleate a polyvalent scaffold and show how PKA signaling is linked to the regulation of transporters. Formation of the D-AKAP2: PKA binary complex is an important first step for high affinity interaction with PDZK1, and the structure reveals important clues toward understanding this phenomenon. In contrast to many other AKAPs, D-AKAP2 does not interact directly with the membrane protein. Instead, the interaction is facilitated by the C-terminus of D-AKAP2, which contains two binding motifs - the D-AKAP2AKB and the PDZ motif - that are joined by a short linker and only become ordered upon binding to their respective partner signaling proteins. The D-AKAP2AKB binds to the D/D domain of the R-subunit and the C-terminal PDZ motif binds to a PDZ domain (from PDZK1) that serves as a bridging protein to the transporter. This structure also provides insights into the fundamental question of why D-AKAP2 would exhibit a differential mode of binding to the two PKA isoforms.

Original languageEnglish
Pages (from-to)105-116
Number of pages12
JournalProtein Science
Issue number1
StatePublished - 1 Jan 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2014 The Protein Society.


FundersFunder number
American Heart Association0825041F
National Institutes of HealthDK054441
National Institute of General Medical SciencesR01GM034921


    • A-kinase anchoring proteins
    • AKAP10
    • D-AKAP2 specificity
    • PDZK1 crystal structure
    • PKA signaling


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