Spectrin. (A) Organization of erythrocyte spectrin and the dimer-tetramer equilibrium. Spectrin is a long, flexible, wormlike protein composed of 2 chains (α- and β-spectrin). Each chain contains a tandem array of ∼5.0-nm, ∼106-amino acid, triple-helical spectrin-type repeats, with specialized functional domains for self-association and ankyrin-1 binding at the head end, and for binding to actin, protein 4.1R, and other associated proteins at the tail end. Each spectrin repeat is formed by 3 α-helices (A, B, and C) with short connecting loops that are folded like a flattened Z into a triple-helical bundle.¹²  α-Spectrin contains 21 numbered repeats (α1-α21), plus a partial repeat (α0) at the N-terminus that contains a single C-helix. One of the 21 is really an src homology 3 (SH3) domain (α10) but is numbered as a repeat by convention. β-Spectrin contains 16 true repeats (β1-β16) plus a partial repeat (β17) at the C-terminus that contains just the A and B helices. Note that for the spectrin αβ dimer to convert to the α₂β₂ tetramer, it must first cleave the internal linkage between the partial spectrin repeats α0 and β17 and then unfold (open dimer).¹³  This is the rate-limiting step in the dimer-tetramer equilibrium. Dimer-tetramer self-association occurs at the head end of the spectrin dimer where the adhesion protein Lutheran/basal cell adhesion molecule (Lu/BCAM) also attaches.¹⁴  Ankyrin-1 binds nearby to spectrin repeats β14-β15.¹⁵  These 2 reactions cooperate: ankyrin-binding favors spectrin tetramer formation, and vice versa.¹⁶  The isolated α- and β-spectrin chains join to form spectrin heterodimers at a nucleation site near the tail end of spectrin (repeats α-21 pairs with β-1, and α-20 with β-2) and then zip together in a cooperative manner.¹⁷  Actin and protein 4.1R bind to CH domains at the N-terminal end of β-spectrin, just beyond the nucleation site.¹⁸  Binding to the CH2 domain is activated by phosphatidylinositol-4,5-bisphosphate (PIP₂).¹⁸  Adducin binds in the same region.¹⁹  Protein 4.2 and calcium ion (Ca²⁺) bind to a neighboring EF hand domain on α-spectrin.⁵  Both the EF hand and CH domains are needed for full actin binding.^20,21  PS denotes spectrin repeats that bind phosphatidyl serine.²²  Blue stars mark repeats that are relatively unstable at physiological temperatures.²³  (B) Structure of spectrin repeats β8 and β9 (PDB 1S35²⁴ ). Note that each repeat is formed by 3 α-helices (A, B, and C) in a Z configuration. Note also that helix C in β8 and helix A in β9 form a continuous α-helix that spans the junction between the repeats. (C) Hypothetical model of the tail end of spectrin based on recent structures of α-actinin.^25,26  Note that the first actin-binding domain (CH1) binds to F-actin in an extended (open) conformation.²⁶  The intimate relationship between the EF hand and CH domains and the recent evidence that the EF hand domain is required for optimal spectrin-actin binding^20,21  suggest that the EF hand domains regulate actin binding.