BUB3
Encyclopedia
Mitotic checkpoint protein BUB3 is a protein
that in humans is encoded by the BUB3 gene
.
Bub3 is a protein involved with the regulation of the Spindle Assembly Checkpoint (SAC)
; though BUB3 is non-essential in yeast, it is essential in higher eukaryotes. As one of the checkpoint proteins, Bub3 delays the irreversible onset of anaphase
through direction of kinetochore
localization during prometaphase
to achieve biorentation. In directing the kinetochore-microtubule interaction, this ensures the proper (and consequenctly, bioriented) attachment of the chromosomes prior to anaphase. Bub3 and its related proteins that form the Spindle Assembly Checkpoint (SAC) inhibit the action of the Anaphase Promoting Complex (APC)
, preventing early anaphase entry and mitotic exit; this serves as a mechanism for the fidelity of chromosomal segregation.
s, with each blade formed by four anti-parallel beta sheet
strands that have been organized around a tapered channel. Mutation data suggest several important surfaces of interaction for the formation of the SAC, particularly the conserved tryptophans (in blades 1 and 3) and the conserved VAVE sequences in blade 5.
Rae1
(an mRNA export factor), another member of the WD40
protein family, shows high sequence conservation with that of Bub3. Both share a Gle2p-binding-sequence (GLEBS) motif; while Bub3 specifically binds Mad3 and Bub1
, Rae1 has more promiscuous binding as it binds both the nuclear pore complex and Bub1. This indicates a similarity in interaction of Bub3 and Rae1 with Bub1.
, HDAC1
and Histone deacetylase 2
.
Bub3 has been shown to form complexes with Mad1
-Bub1 and with Cdc20
(the interaction of which does not require intact kinetochores). Additionally, it has been shown to bind Mad2
and Mad3.
Bub3 directs the localization of Bub1 at the kinetochore in order to activate the SAC. In both Saccharomyces cerevisiae
and metazoans, Bub3 has been show to bind BubR1 and Bub1
Bub3 also acts as a regulator in that it affects binding of Mad3 to Mad2.
Structural and sequence analysis indicated the existence of three conserved regions that are referred to as WD40 repeats. Mutation of one of these motifs has indicated an impaired ability of Bub3 to interact with Mad2, Mad3, and Cdc20. The structural data suggested that Bub3 acts as a platform that mediates the interaction of SAC protein complexes.
and cyclin B
are also stabilized before the anaphase transition by the unattached kinetochores. The stabilization of cyclin and securin prevent the degradation that would lead to the irreversible and fast separation of the sister chromatids
.
The formation of these “inhibitory complexes” and steps feed into a ‘wait’ signal before activation of separase
; at the stage prior to anaphase, securin inhibits the activity of separase and maintains the cohesion
complex.
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...
that in humans is encoded by the BUB3 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...
.
Bub3 is a protein involved with the regulation of the Spindle Assembly Checkpoint (SAC)
Spindle checkpoint
In order to preserve one cell's identity and its proper functioning, it is necessary to maintain constant the appropriate number of chromosomes after each cell division...
; though BUB3 is non-essential in yeast, it is essential in higher eukaryotes. As one of the checkpoint proteins, Bub3 delays the irreversible onset of 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....
through direction of kinetochore
Kinetochore
The kinetochore is the protein structure on chromatids where the spindle fibers attach during cell division to pull sister chromatids apart....
localization during prometaphase
Prometaphase
Prometaphase is the phase of mitosis following prophase and preceding metaphase, in eukaryotic somatic cells. In Prometaphase, The nuclear envelope breaks into fragments and disappears. The tiny nucleolus inside the nuclear envolope, also dissolves. Microtubules emerging from the centrosomes at the...
to achieve biorentation. In directing the kinetochore-microtubule interaction, this ensures the proper (and consequenctly, bioriented) attachment of the chromosomes prior to anaphase. Bub3 and its related proteins that form the Spindle Assembly Checkpoint (SAC) inhibit the action of the Anaphase Promoting Complex (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...
, preventing early anaphase entry and mitotic exit; this serves as a mechanism for the fidelity of chromosomal segregation.
Structure
The crystal structure of Bub3 indicates a protein of the seven-bladed beta-propeller structure with the presence of WD40 repeatWD40 repeat
The WD40 repeat is a short structural motif of approximately 40 amino acids , often terminating in a tryptophan-aspartic acid dipeptide...
s, with each blade formed by four anti-parallel beta sheet
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
strands that have been organized around a tapered channel. Mutation data suggest several important surfaces of interaction for the formation of the SAC, particularly the conserved tryptophans (in blades 1 and 3) and the conserved VAVE sequences in blade 5.
Rae1
RAE1
mRNA export factor is a protein that in humans is encoded by the RAE1 gene.blair.s- Further reading :...
(an mRNA export factor), another member of the WD40
WD40 repeat
The WD40 repeat is a short structural motif of approximately 40 amino acids , often terminating in a tryptophan-aspartic acid dipeptide...
protein family, shows high sequence conservation with that of Bub3. Both share a Gle2p-binding-sequence (GLEBS) motif; while Bub3 specifically binds Mad3 and Bub1
BUB1
Mitotic checkpoint serine/threonine-protein kinase BUB1 also known as BUB1 is an enzyme that in humans is encoded by the BUB1 gene....
, Rae1 has more promiscuous binding as it binds both the nuclear pore complex and Bub1. This indicates a similarity in interaction of Bub3 and Rae1 with Bub1.
Interactions
BUB3 has been shown to interact with BUB1BBUB1B
Mitotic checkpoint serine/threonine-protein kinase BUB1 beta is an enzyme that in humans is encoded by the BUB1B gene.-Interactions:BUB1B has been shown to interact with AP2B1, HDAC1, BUB3, MAD2L1, Gamma-synuclein, BRCA2 and CDC20.-Further reading:...
, HDAC1
HDAC1
Histone deacetylase 1 is an enzyme that in humans is encoded by the HDAC1 gene.-Interactions:HDAC1 has been shown to interact with RAD9A, DNMT3L, MTA1, FKBP3, CDC20, CDH1, Host cell factor C1, BUB3, Nuclear receptor co-repressor 2, IKZF1, Prohibitin, EVI1, DDX5, DNMT3A, Mothers against...
and Histone deacetylase 2
Histone deacetylase 2
Histone deacetylase 2 is an enzyme that in humans is encoded by the HDAC2 gene.-Interactions:Histone deacetylase 2 has been shown to interact with CHD3, MTA1, FKBP3, CHD4, RCOR1, Retinoblastoma protein, CDC20, RBBP4, CDH1, EED, GTF2I, Host cell factor C1, PHF21A, BUB3, MXD1, HDAC10, RELA, Sp3...
.
Bub3 has been shown to form complexes with Mad1
Mad1
Mitotic spindle assembly checkpoint protein MAD1 is a protein that in humans is encoded by the MAD1L1 gene.MAD1L1 is also known as Human Accelerated Region 3. It may therefore have played a key role in differentiating Humans from Apes.-Interactions:...
-Bub1 and with Cdc20
CDC20
The cell-division cycle protein 20 is an essential regulator of cell division that is encoded by the CDC20 gene in humans. To the best of current knowledge its most important function is to activate the anaphase promoting complex , a large 11-13 subunit complex that initiates chromatid separation...
(the interaction of which does not require intact kinetochores). Additionally, it has been shown to bind Mad2
MAD2
MAD2 is an essential spindle checkpoint protein. The spindle checkpoint system is a regulatory system that restrains progression through the metaphase-to-anaphase transition. The Mad2 gene was first identified in the yeast S. cerevisiae in a screen for genes which when mutated would confer...
and Mad3.
Bub3 directs the localization of Bub1 at the kinetochore in order to activate the SAC. In both Saccharomyces cerevisiae
Saccharomyces 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...
and metazoans, Bub3 has been show to bind BubR1 and Bub1
Bub3 also acts as a regulator in that it affects binding of Mad3 to Mad2.
Structural and sequence analysis indicated the existence of three conserved regions that are referred to as WD40 repeats. Mutation of one of these motifs has indicated an impaired ability of Bub3 to interact with Mad2, Mad3, and Cdc20. The structural data suggested that Bub3 acts as a platform that mediates the interaction of SAC protein complexes.
Role in the Spindle Assembly Checkpoint
At unattached kinetochores, a complex consisting of BubR1, Bub3, and Cdc20 interact with the Mad2-Cdc20 complex to inhibit the APC, thus inhibiting the formation of active APCCdc20. Bub3 binds constitutively to Bub1; in this arrangement, Bub3 acts as a key component of the SAC in the formation of an inhibitory complex. SecurinSecurin
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...
and cyclin B
Cyclin B
Cyclin B is a member of the cyclin family.Cyclin B is a mitotic cyclin. The amount of cyclin B and the activity of the cyclin B-Cdk complex rise through the cell cycle until mitosis, where they fall abruptly due to degradation of cyclin B...
are also stabilized before the anaphase transition by the unattached kinetochores. The stabilization of cyclin and securin prevent the degradation that would lead to the irreversible and fast separation of the 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...
.
The formation of these “inhibitory complexes” and steps feed into a ‘wait’ signal before activation of separase
Separase
Separase is a cysteine protease responsible for triggering anaphase by hydrolysing cohesin which is the protein responsible for binding sister chromatids during metaphase. In humans, separase is encoded by the ESPL1 gene.- Discovery :...
; at the stage prior to anaphase, securin inhibits the activity of separase and maintains the cohesion
Cohesion
Cohesion may refer to:* Cohesion , the intermolecular attraction between like-molecules* Cohesion , a measure of how well the lines of source code within a module work together...
complex.