Beyond PKA: Scaffolding the subcellular architecture

Protein interaction domains create unique macromolecular complexes that drive evolution.  By combining phylogenetic analyses with structural approaches, we have discovered that the docking and dimerization (D/D) domain of the protein kinase A regulatory (PKA-R) subunit is an ancient protein fold.  Homology searching reveals a D/D domain superfamily with eighteen members that are conserved across most metazoan phyla.  These proteins segregate into subgroups based on their similarity to type I or type II PKA-R subunits.  The sperm autoantigenic protein 17 (SPA17) is a prototype of the type II or R2D2 subgroup.  This cell-surface protein binds to the zona pellucida of the oocyte during fertilization.  The crystal structure of SPA17 revealed a four-polypeptide configuration that can cross link to AKAPs and other protein components.  Thus, the D/D fold as a versatile protein interaction element that stabilizes macromolecular architectures within motile organelles such as sperm, flagella and cilia.

For more details:  Dahlin HR, Zheng N, Scott JD. (2021) Beyond PKA: Evolutionary and Structural Insights that Define a Docking and Dimerization Domain Superfamily. J. Biol. Chem. 297: 100927. https://pubmed.ncbi.nlm.nih.gov/34256050/.