In biologic protease substrates, additional factors outside the 4 amino acid recognition site can influence the selectivity and efficiency of proteolytic cleavage. For caspases, it has been shown that the amino acid residue directly after the scissile bond (P19) is an important determinant of cleavage, since charged or bulky residues are not well tolerated [7] . Furthermore, domains far away from the cleavage site can mediate the interaction between substrate and protease (exosites), and although such interactions have not yet been shown for proteases of the caspase family, the high variability of cleavage site motifs in natural caspase substrates argues in favour of the presence of exosites. Known substrates for caspase-6 show a particularly high variability in their recognition sequences [8] , with cleavage sites other than I/D/E/L/T/V, E/ D/Q, X, D found in substrates such as the presenilins (ENDD, [9] ), huntingtin (IVLD, [10] ), DNA Topoisomerase I (PEDD, [11] ), AP-2 alpha (DRHD, [12] ), Periplakin (TVAD, [13] ), FAK (VSWD, [14] ) and TGEV (VVPD, [15] ).