Figure 4. Mad2 conversion and the kinetic barrier to C-Mad2:Cdc20 association.

(a) The conformational rearrangement of Mad2 during the O-Mad2 to C-Mad2 transition. On the left O-Mad2 is depicted, and on the right C-Mad2 with the Mad2-interacting motif (MIM) entrapped by the safety belt of Mad2 (PDB 2V64).⁸⁴ The crystal structure was determined in the presence of a MIM peptide selected for its enhanced C-Mad2 affinity using phage display.⁸³ The N- and C-terminal segments which undergo remodeling during Mad2 conversion are colored in yellow and red, respectively. (b-d) Schematics outlining relative rates at cellular concentrations of Mad2 conversion and C-Mad2: Cdc20 formation with or without ligand (Cdc20) and catalysts. (b) Conversion of O-Mad2 by itself into C-Mad2 is kinetically disfavored and thus conversion occurs very slowly. (c) Conversion of O-Mad2 and C-Mad2:Cdc20 association in the presence of full-length Cdc20 without accompanying catalysts is limited by the disfavoured and rate-limiting spontaneous conversion of Mad2 which is required to form C-Mad2: Cdc20. (d) Conversion of O-Mad2 and concomitant C-Mad2:Cdc20 formation is rapid in the presence of identified catalysts (Bub1, Mad1:C-Mad2, and Mps1 phosphorylation).