Separase
Encyclopedia
Separase is a cysteine
protease
responsible for triggering anaphase
by hydrolysing cohesin
which is the protein
responsible for binding sister chromatid
s during metaphase
. In humans, separase is encoded by the ESPL1 gene
.
, separase is encoded by the Esp1 gene. Esp1 was discovered by Kim Nasmyth
and coworkers in 1998.
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 apart 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
.
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.
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
responsible for triggering anaphase
Anaphase
Anaphase, from the ancient Greek ἀνά and φάσις , is the stage of mitosis or meiosis when chromosomes move to opposite poles of the cell....
by hydrolysing cohesin
Cohesin
Cohesin is a protein complex that regulates the separation of sister chromatids during cell division, either mitosis or meiosis.- Structure :...
which is the protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
responsible for binding sister chromatid
Chromatid
A chromatid is one of the two identical copies of DNA making up a duplicated chromosome, which are joined at their centromeres, for the process of cell division . They are called sister chromatids so long as they are joined by the centromeres...
s during metaphase
Metaphase
Metaphase, from the ancient Greek μετά and φάσις , is a stage of mitosis in the eukaryotic cell cycle in which condensed & highly coiled chromosomes, carrying genetic information, align in the middle of the cell before being separated into each of the two daughter cells...
. In humans, separase is encoded by the ESPL1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Discovery
In S. cerevisiaeSaccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
, separase is encoded by the Esp1 gene. Esp1 was discovered by Kim Nasmyth
Kim Nasmyth
Professor Kim Nasmyth FRS is the Whitley Professor of Biochemistry . Nasmyth was formerly the Director of the Research Institute of Molecular Pathology in Vienna, Austria and the Head of the Department of Biochemistry of the University of Oxford...
and coworkers in 1998.
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 STAG1STAG1
Cohesin subunit SA-1 is a protein that in humans is encoded by the STAG1 gene.-Further reading:...
or STAG2
STAG2
Cohesin subunit SA-2 is a protein that in humans is encoded by the STAG2 gene.-Further reading:...
in the cohesin complex. The second step involves cleavage of the cohesin subunit SCC1 (RAD21
RAD21
Double-strand-break repair protein rad21 homolog is a protein that in humans is encoded by the RAD21 gene.-External links:...
) 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
Securin
Securin is a protein involved in control of the metaphase-anaphase transition and anaphase onset. Following bi-orientation of chromosome pairs and inactivation of the spindle checkpoint system, the underlying regulatory system, which includes securin, produces an abrupt stimulus that induces highly...
Pds1. The two sister chromatids are initially bound together by the cohesin complex until the beginning of anaphase, at which point the mitotic spindle
Mitotic spindle
In cell biology, the spindle fibers are the structure that separates the chromosomes into the daughter cells during cell division. It is part of the cytoskeleton in eukaryotic cells...
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 apart of the cohesin
Cohesin
Cohesin is a protein complex that regulates the separation of sister chromatids during cell division, either mitosis or meiosis.- Structure :...
protein family. One of these cohesin proteins crucial for sister chromatid cohesion is Scc1. Esp1 is a separase protein that cleaves the cohesin
Cohesin
Cohesin is a protein complex that regulates the separation of sister chromatids during cell division, either mitosis or meiosis.- Structure :...
subunit Scc1 (RAD21), allowing sister chromatids
Sister chromatids
Sister chromatids are two identical copies of a chromatid connected by a centromere. Compare sister chromatids to homologous chromosomes, which are the two different copies of the same chromosome that diploid organisms inherit, one from each parent...
to separate at the onset of anaphase during mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
.
Regulation
When the cell is not dividing, separase is prevented from cleavingCleave
Cleave may refer to:*Cleave , a controlled break in optical fiber*RAF Cleave, airbase in Cornwall, England, 1939-1945-People with surname Cleave:*Chris Cleave , British journalist*Egbert Cleave , American author...
cohesin through its association with another protein, securin
Securin
Securin is a protein involved in control of the metaphase-anaphase transition and anaphase onset. Following bi-orientation of chromosome pairs and inactivation of the spindle checkpoint system, the underlying regulatory system, which includes securin, produces an abrupt stimulus that induces highly...
, 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
Anaphase-promoting complex
Anaphase-Promoting Complex, also called cyclosome , is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. The APC/C is a large complex of 11–13 subunit proteins, including a cullin and RING subunit much like SCF...
-Cdc20 complex. Active separase can then cleave Scc1 for release of the sister chromatids.
Separase initiates the activation of Cdc14
Cdc14
Cdc14 was defined by Hartwell in his famous screen for loci that control the cell cycle of Saccharomyces cerevisiae. Cdc14 was later shown to encode a protein phosphatase. Cdc14 is dual-specificity, which means it has serine/threonine and tyrosine-directed activity. A preference for serines...
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.
External links
- http://www.ncbi.nih.gov/entrez/query.fcgi?db=nucleotide&cmd=search&term=L07289&doptcmdl=GenBank