ankyrin

Ankyrins are a family of adaptor proteins that connect integral membrane proteins to the spectrin–actin cytoskeleton. There are three major vertebrate ankyrin genes: ANK1 (ankyrin-1), ANK2 (ankyrin-2, ankyrin-B), and ANK3 (ankyrin-3, ankyrin-G). They are widely expressed but have tissue-enriched isoforms: ankyrin-R in erythrocytes; ankyrin-B in the heart and brain; ankyrin-G in neurons, especially at the axon initial segment and nodes of Ranvier.

They share a modular architecture: an N-terminal region containing ankyrin repeats that mediates interactions with diverse membrane proteins; a central ZU5-UPA domain; and a C-terminal regulatory tail that binds spectrin and other cytoskeletal components. Through these domains, ankyrins serve as scaffolds that stabilize and localize membrane proteins such as voltage-gated sodium channels (e.g., Nav1.1/1.2/1.7) and other transporters and adhesion molecules.

Functions: organizing membrane domains, regulating trafficking and localization of ion channels and transporters, maintaining the integrity of membrane–cytoskeleton connections. In neurons, ankyrin-G coordinates the assembly of the axon initial segment and nodes of Ranvier by tethering voltage-gated channels and cell-adhesion molecules to the cytoskeleton.

Clinical significance: ANK1 mutations cause hereditary spherocytosis; ANK2 variants are linked to cardiac arrhythmias and metabolic disturbances; ANK3 variants have been associated with schizophrenia and mood disorders in genetic studies, though mechanisms remain under investigation.