It has been proposed that the TPR repeats interact with the isoleucine and arginine selleck chem Paclitaxel rich motifs found in the C terminal regions of adaptors co activators. The TPR arm may also contain Apc16, a subunit recently reported by the MitoCheck consortium. Finally, the location of Apc14, a yeast essential subunit remains undetermined. The APC C activity and specificity are modulated by several adaptors co activators. These are paralogous proteins containing WD repeats that mediate the interaction between the APC C and the D, KEN, A or O boxes present on target sub strates. Among those adaptors, Cdc20 and Cdh1 are the most important, being directly involved in the activation and substrate selectivity of the APC C at different stages of the cell cycle.

The interaction of the APC C and either Cdc20 or Cdh1 is strongly dependent on the high or low activity of Cdks. Briefly, Cdc20 activates the APC C during early mitosis once the chromosomes are properly attached and bi oriented at the metaphase plate during a process known as the spindle assembly checkpoint. The APC C Cdc20 targets securins and cyclins B1 towards destruction by the proteasome. The degradation of these two proteins promotes the activation of separases, which then cleave the cohesin complex leading to the separation of sister chromatids and the initiation of the anaphase. During anaphase, the APC C Cdh1 targets Polo like kinase 1, Aurora kinases, mitotic cyclins and Cdc20 towards degradation leading to the exit of mitosis. The APC C Cdh1 remains active during the G1 S phase ensuring the degradation by the 26S proteasome of several inhibitors of DNA replication, thus allowing the synthesis of DNA.

At the end of the S phase, the increase of the activity of Cdks inhibits the interaction between Cdh1 and the APC C complex, precluding new rounds of DNA synth esis. By contrast, other APC C activators seem to have more restricted roles, Ama1 is required for sporu lation and during the anaphase of meiosis I in budding yeast, Mfr1 acts at the end of meiosis II in S. pombe, Cortex encodes a putative Drosophila mela nogaster female meiosis specific co activator of the APC C prior to the metaphase I arrest and, finally, Rap mediates the degrada tion of cyclins during the development of eye imaginal discs in D. melanogaster.

If most of the APC C studies have been carried out in yeast and animals, recent experiments with the land plant Arabidopsis thaliana have allowed the identifica tion of 12 transcribed genes that are homologous to ver tebrate and yeast APC C subunits and of eight Cdh1 Cdc20 homologues. By contrast, very little information is available for representatives of the other major eukaryotic lineages. The only exception concerns the kinetoplastid species Trypanosoma brucei, shown to encode seven APC C subunit Carfilzomib homologues in its genome.