|PDB structures||RCSB PDB PDBe PDBsum|
|Extra spindle pole bodies homolog 1 (S. cerevisiae)|
Separase also known as separin is a cysteine protease responsible for triggering anaphase by hydrolysing cohesin which is the protein responsible for binding sister chromatids during metaphase. In humans, separin is encoded by the ESPL1 gene.
Stable cohesion between sister chromatids before anaphase and their timely separation during anaphase are critical for cell division and chromosome inheritance. In vertebrates, sister chromatid cohesion is released in 2 steps via distinct mechanisms. The first step involves phosphorylation of STAG1 or STAG2 in the cohesin complex. The second step involves cleavage of the cohesin subunit SCC1 (RAD21) by separase, which initiates the final separation of sister chromatids.
In S. cerevisiae, Esp1 is coded by esp1-1 and is regulated by the securin Pds1. The two sister chromatids are initially bound together by the cohesin complex until the beginning of anaphase, at which point the mitotic spindle pulls the two sister chromatids apart, leaving each of the two daughter cells with an equivalent number of sister chromatids. The proteins that bind the two sister chromatids, disallowing any premature sister chromatid separation, are a part of the cohesin protein family. One of these cohesin proteins crucial for sister chromatid cohesion is Scc1. Esp1 is a separase protein that cleaves the cohesin subunit Scc1 (RAD21), allowing sister chromatids to separate at the onset of anaphase during mitosis.
When the cell is not dividing, separase is prevented from cleaving cohesin through its association with another protein, securin, as well as phosphorylation by the cyclin-CDK complex. This provides two layers of negative regulation to prevent inappropriate cohesin cleavage. Interestingly, separase cannot function without initially forming the securin-separase complex in most organisms. This is because securin helps properly fold separase into the functional conformation. However, yeast does not appear to require securin to form functional separase because anaphase occurs in yeast even with a securin deletion.
On the signal for anaphase, securin is ubiquitinated and hydrolysed, releasing separase for dephosphorylation by the APC-Cdc20 complex. Active separase can then cleave Scc1 for release of the sister chromatids.
Separase initiates the activation of Cdc14 in early anaphase and Cdc14 has been found to dephosphorylate securin, thereby increasing its efficiency as a substrate for degradation. The presence of this positive feedback loop offers a potential mechanism for giving anaphase a more switch-like behavior.
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- separase at the US National Library of Medicine Medical Subject Headings (MeSH)
- Video by David Morgan explaining action of securin and separin (in MP4 format): http://media.hhmi.org/ibio/morgan/morgan_3.mp4
- and in other formats: http://www.ibioseminars.org/lectures/bio-mechanisms/david-morgan-part-1/david-morgan-part-3.html