The first extracellular repeat of cadherin-23 structurally defines a family of cadherin proteins. (A) Sequence alignment of EC1 from the cadherin-related families 2 and 3 (Cr-2 and Cr-3, respectively) and classical cadherins (C-1). Alignment notations are as in Figure 1A. Cr-2 members protocadherin-21 and protocadherin-24 feature elongated N-termini and share critical conserved cadherin-23 residues involved in Ca2+-binding site 0 (red boxes). Protocadherin-15's extended N-terminus is likely involved in a disulfide bridge instead (yellow boxes), and has three acidic residues encoded by exon 2, and another two by exon 3 (sometimes spliced out as shown for the human sequence). NCBI reference sequences: NP_570948.1, NP_001028536.1, NP_075859.2, NP_149045.3, NP_075604.2, NP_001038119.1, NP_001080946.1, NP_033994.1, BAA23549.1, NP_001034243.1, NP_033996.4. (B) Molecular surface representation of EC1 repeats from cadherin-23 (left) and classical type I C-cadherin (right, pdb code 1L3W, Boggon et al. (2002)), with the N-terminal ß-strands shown in blue (cadherin-23) or white (C-cadherin) cartoon. Cadherin-23 EC1 displays an elongated N-terminus and lacks the characteristic tryptophan residues at position 2 (W2) of classical type I cadherins (or positions 2 & 4 of classical type II cadherins). A piece of the N-terminus and W2 of the interacting C-cadherin protomer is shown in red. (C) Superposition of cadherin-23 EC1 (blue) with C-cadherin EC2 (grey). The location of the cadherin-23 EC1 Ca2+-binding site 0 matches that of classical cadherin site 3. (D,E) Detail of the cadherin-23 site 0 and C-cadherin Ca2+-binding site 3, respectively, with residues coordinating Ca2+ ions in stick. The overall architecture of both Ca2+-binding sites is similar, but C-cadherins's N143 carbonyl oxygen is replaced by cadherin-23's D40 side-chain.