Surface mapping of important sites onto the three-dimensional structure of annexins. All panels show the crystal structure of the core region of the pig annexin A1 protein (Protein Data Bank code:1MCX ), viewed frontally (left) and laterally inverted (right) as a space-filling model rendered by the RasTop 2.0 version of RasMol . Residues are numbered as in Figure 2, and the approximate positions of the conserved repeats are indicated with Roman numerals. (a) Functionally important sites common to all annexins. The level of evolutionary conservation in clusters of residues is indicated by lighter or darker shading. This is derived from a maximum-likelihood analysis of a multiple sequence alignment from 200 vertebrate A-family annexins using CONSURF [22, 23] NT, amino terminus. (b) Sites that are functionally divergent between annexin subfamilies are shown with different shading for ANXA1, ANXA2 or ANXA5, three annexins for which the differences are especially significant. The sites were assessed by 'rate-shift analysis' of subfamily sequence alignments using DIVERGE  RATE4SITE and CONSURF [22, 23]. Calcium atoms are indicated by Ca.