Ankyrin. (A) Schematic of erythroid ankyrin structure.⁷⁰  The membrane domain contains 24 ankyrin repeats, grouped functionally into 4 subdomains of 6 repeats. There are 2 binding sites for band 3, one involving repeats 7 to 12 (domain D2), and one involving repeats 13 to 24 (D3/D4). The ankyrin binding loops on band 3 are predicted to interact with ankyrin repeats 19 and 20 (light blue) of D4.⁷¹  The interaction site within D2 is not known. The spectrin domain contains 3 subdomains, of which ZU5A (light blue) contains the binding site for spectrin.^15,72  The C-terminal (regulatory) domain is thought to modulate the binding functions of the other 2 domains,^70,73  and exists in numerous spliced variants of mostly unknown function. The function of the conserved death domain (DD) is also a mystery. (B) Hypothetical model⁷⁴  of the interaction between the membrane domain of ankyrin (green) and a band 3 tetramer (red, blue, cyan, and purple subunits). Note how the ankyrin repeats form a large (9-nm diameter) twisted helical spiral. In this deduced model, the concave surface of the D3/D4 region interacts with the red subunit in 1 band 3 dimer. One subunit in the second band 3 dimer contacts the concave surface of the D2 region, which contains a second band 3 binding site. (C) Spectrin-ankyrin interaction. Note how ZU5A, the spectrin-binding subdomain within ankyrin, binds in the notch created by the sharp angle between spectrin repeats β14 and β15. Panel B reprinted from Michaely et al⁷⁴  and panel C from Ipsaro and Mondragón,¹⁵  both with permission.