Coordination between discrete Mitotic Arrest Deficient 1 (MAD1) domains is required for efficient mitotic checkpoint signaling

Wenbin Ji; Yibo Luo; Ejaz Ahmad; Song-Tao Liu

The crystal structure of MAD1-MIM in complex with C-MAD2 has solidified the now classical model of the MAD1:C-MAD2 catalyst as a 2:2 heterotetramer (11) ( Fig S1) . Each of the two "liganded" C-MAD2 tightly wraps around one MIM monomer through its "safety belt" loop (11, 18, 38) . C-MAD2 then utilizes its dimerization domain to recruit O-MAD2 and converts the latter into C-MAD2, resulting in signal amplification for the mitotic checkpoint (6, 7, 12) . The conversion may go through multiple intermediate states (I-MAD2) (6, 7, 10, 13, 32) . At least two structures of I-MAD2:C-MAD2 dimers have been solved, one possibly representing the initial O-MAD2 "docking" complex and the other containing a later stage of I-MAD2 state (MAD2 N10 ) (10,32). The major structural features distinguishing O-and C-MAD2 lie at the N-and Ctermini (8) . The solved MAD2 N10 structure indicates a topology similar to O-MAD2 but its internal core more closely resembles that of C-MAD2 (10). However, one long suspected intermediate state with partially unfolded N-or Ctermini, which is more amenable for MAD2 5 All rights reserved. No reuse allowed without permission.