Separase

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 the early stage of anaphase. In humans, separin is encoded by the ESPL1 gene.

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 the early stage of anaphase. In humans, separin is encoded by the ESPL1 gene. ==History== In S. cerevisiae, separase is encoded by the esp1 gene. Esp1 was discovered by Kim Nasmyth and coworkers in 1998. In 2021, structures of human separase were determined in complex with either securin or CDK1-cyclin B1-CKS1 using cryo-EM by scientists of the University of Geneva. ==Regulation== When the cell is not dividing, separase is prevented from cleaving cohesin through its association with either securin or upon phosphorylation of a specific serine residue in separase by the cyclin-CDK complex. Separase phosphorylation leads to a stable association with CDK1-cyclin B1. Securin or CDK1-cyclin B binding is mutually exclusive. In both complexes, separase is inhibited by pseudosubstrate motifs that block substrate binding at the catalytic site and at nearby docking sites. However, while securin contains its own pseudosubstrate motifs to occlude substrate binding, the CDK1–cyclin B complex inhibits separase by rigidifying pseudosubstrate motifs from flexible loops in separase itself, leading to an auto-inhibition of the proteolytic activity of separase. Regulation through these distinct binding partners provides two layers of negative regulation to prevent inappropriate cohesin cleavage. Note that 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. https://web.archive.org/web/20041117073907/http://ncbi.nih.gov/entrez/query.fcgi?db=Nucleotide 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: [https://web.archive.org/web/20110925154452/http://www.ibioseminars.org/lectures/bio-mechanisms/david-morgan-part-1/david-morgan-part-3.html]

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