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ESPL1
Identifiers
Aliases	ESPL1, ESP1, SEPA, EPAS1, Separase, extra spindle pole bodies like 1, separase
External IDs	OMIM: 604143; MGI: 2146156; HomoloGene: 32151; GeneCards: ESPL1; OMA:ESPL1 - orthologs
Gene location (Human)
Chr.	Chromosome 12 (human)
End	53,293,638 bp
Gene location (Mouse)
Chr.	Chromosome 15 (mouse)
End	102,232,792 bp
RNA expression pattern
	Top expressed in
	secondary oocyte; ; ventricular zone; ; jejunal mucosa; ; oral cavity; ; gonad; ; mucosa of ileum; ; embryo; ; gingival epithelium; ; amniotic fluid; ; mucosa of pharynx;
	Top expressed in
	oocyte; ; primary oocyte; ; epiblast; ; secondary oocyte; ; hand; ; ventricular zone; ; seminiferous tubule; ; superior cervical ganglion; ; spermatid; ; spermatocyte;
	More reference expression data
	More reference expression data
Gene ontology
Molecular function	cysteine-type peptidase activity; peptidase activity; catalytic activity; protein binding; cysteine-type endopeptidase activity; hydrolase activity;
Cellular component	cytoplasm; cytosol; centrosome; mitotic spindle; nucleus;
Biological process	negative regulation of sister chromatid cohesion; chromosome segregation; homologous chromosome segregation; proteolysis; positive regulation of mitotic metaphase/anaphase transition; meiotic chromosome separation; meiotic spindle organization; meiosis I; mitotic sister chromatid segregation; establishment of mitotic spindle localization; apoptotic process; mitotic cell cycle; mitotic cytokinesis;
	Sources:Amigo / QuickGO
Orthologs
	9700
	105988
	ENSG00000135476
	ENSMUSG00000058290
	Q14674
	P60330
	NM_012291
	NM_001014976; NM_001356312
	NP_036423
	NP_001014976; NP_001343241
	Wikidata
View/Edit Human	View/Edit Mouse

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PMC	articles
PubMed	articles
NCBI	proteins

Separase
Separase
Identifiers
EC no.	3.4.22.49
CAS no.	351527-77-0
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
PMC
Search
PMC	articles
PubMed	articles
NCBI	proteins

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.^[5] In humans, separin is encoded by the ESPL1 gene.^[6]

History

In S. cerevisiae, separase is encoded by the esp1 gene. Esp1 was discovered by Kim Nasmyth and coworkers in 1998.^[7]^[8] 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.^[9]

Function

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.^[11]

In S. cerevisiae, Esp1 is coded by ESP1 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.^[8]

Regulation

Network diagram with feedback loops to generate switch-like activation of anaphase.^[12]

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.^[9] 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.^[10]

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^[13] 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.^[12]