The ZU5 subdomain is capable of forming multiple, specific interactions with distinct surfaces. (A) Structure of the complex between spectrin (blue) and the ZU5-ANK domain of ankyrin (gold). (B) Structure of the cytoplasmic portion of the netrin receptor UNC5b (ZU5-2 domain in magenta, UPA domain in green, DD domain in purple) in the same orientation as panel A. (C) Superposition of the ZU5 domains of the 2 structures demonstrates that ZU5 domains have been adapted to bind multiple ligands with the use of different molecular surfaces. Note that recent sequence analysis of ankyrin R has revealed 2 tandem ZU5 domains⁴⁸ : ZU5-ANK, which binds to spectrin, and a second ZU5 domain (ZU5-2). On the basis of this alignment, the ZU5 domain in the UNC5b structure correlates with the ZU5-2 domain of ankyrin. The superimposition of the models shown in panel C therefore does not reflect a predicted macromolecular assembly; it serves only to demonstrate that distinct interaction surfaces of ZU5 domains have now been observed.