![]() ![]() The SAC is more intricately regulated in higher eukaryotes, and additional components to the core SAC module have been shown to contribute to the SAC in mammalian cells. ![]() In addition, the evolutionary paths of Mad3 and its orthologue BubR1 appear to have diverged considerably BubR1 in higher eukaryotes has a kinase domain that, at least in vertebrates, appears to have degenerated into a pseudokinase. elegans, and it has been hypothesized that, in this organism, the functions of Mps1 may be fulfilled by other kinases such as Polo-like kinase 1 (Plk1). One striking exception is the complete absence of an Mps1 orthologue in C. ![]() These proteins are well-conserved throughout evolution. In addition, numerous data suggest the Aurora B is also a core component of the SAC. Īs indicated above, the major components of this surveillance mechanism, originally identified in budding yeast, include Mad1, Mad2, Mad3 (the budding yeast orthologue of BubR1), Bub1, Bub3 and Mps1. In prometaphase, after nuclear envelope breakdown, at least two different phosphatases, PP1 and PP2A, are recruited at the kinetochores via various adaptor subunits to counteract kinase activity and to locally silence the SAC. Mad1-Mad2 catalyzes the conversion of Mad2 from an inactive, open-like conformation to an active, closed-like conformation, thereby favoring the formation of the MCC. This complex will then recruit the Bub3-BubR1 complex, Cdc20 and Mad-Mad2. The Bub3-Bub1 complex recognizes and docks at these phosphorylated MELT sequences. Mps1 phosphorylates the outer kinetochore protein Kinetochore null 1 (Knl1) at several Met-Glu-Leu-Thr (MELT) motifs, creating docking sites for the recruitment and formation of the MCC which consists of mitotic arrest deficient 2 (Mad2), budding uninhibited by benzimidazoles related 1 (BubR1), budding uninhibited by benzimidazole 3 (Bub3) and cell division cycle 20 (Cdc20). The phosphorylation of the N-terminal tail region of Nuclear division cycle 80/High expression in cancer 1 (Ndc80/Hec1) by Aurora B leads to the recruitment of Mps1 at the kinetochore. During prophase, the checkpoint kinase Monopolar spindle 1 (Mps1) phosphorylates its substrates to activate the SAC, while Aurora B kinase, the catalytic subunit of chromosome passenger complex (CPC), phosphorylates the targets at improperly attached kinetochores to promote error correction. Biochemically, the SAC generates a diffusible, cytoplasmic mitotic checkpoint complex (MCC), a so-called “wait anaphase” signal, that ultimately results in the inhibition of the E3 ubiquitin ligase Anaphase Promoting Complex/Cyclosome (APC/C), hence prolonging the mitotic state. The SAC restrains cells from entering anaphase until all sister chromatids are attached to the microtubules radiating from the two opposite poles of the mitotic spindle. Another important function of the kinetochore is to initiate Spindle Assembly Checkpoint (SAC) signaling. Kinetochores function to align sister chromatids in prometaphase and to pull the sister chromatids apart in anaphase by connecting the chromosomes to microtubules of the spindle. Kinetochores, the large protein complexes that assemble at the centromere of a chromosome, are an essential protein machinery that orchestrates faithful mitosis. During cell division, it is crucial to transmit the duplicated genome to two daughter cells equally. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |