Stathmin, also known as metablastin and oncoprotein 18 is a
protein that in humans is encoded by the STMN1gene.
Stathmin is a
highly conserved 17
kDaprotein that is crucial for the regulation of the cell
cytoskeleton. Changes in the cytoskeleton are important because the cytoskeleton is a scaffold required for many cellular processes, such as cytoplasmic organization,
cell division and
cell motility.[5] More specifically, stathmin is crucial in regulating the
cell cycle.[6] It is found solely in
eukaryotes.
Its function as an important regulatory protein of
microtubule dynamics has been well-characterized.[7] Eukaryotic microtubules are one of three major components of the cell's
cytoskeleton. They are highly dynamic structures that continuously alternate between assembly and disassembly. Stathmin performs an important function in regulating rapid microtubule remodeling of the cytoskeleton in response to the cell's needs. Microtubules are cylindrical polymers of α,β-tubulin. Their assembly is in part determined by the concentration of free
tubulin in the
cytoplasm.[8]
At low concentrations of free tubulin, the growth rate at the microtubule ends is slowed and results in an increased rate of depolymerization (disassembly).[7][9]
Structure
Stathmin, and the related
proteins SCG10 and XB3, contain a N-terminal
domain (XB3 contains an additional N-terminal hydrophobic region), a 78
amino acidcoiled-coil region, and a short C-terminal domain.
Function
The function of Stathmin is to regulate the
cytoskeleton of the
cell. The cytoskeleton is made up of long hollow cylinders named
microtubules. These microtubules are made up of alpha and beta
tubulinheterodimers. The changes in cytoskeleton are known as microtubule dynamics; the addition of the tubulin subunits lead to polymerisation and their loss, depolymerisation.[5] Stathmin regulates these by promoting depolymerization of microtubules or preventing polymerization of tubulin heterodimers.[6]
Stathmin interacts with two molecules of dimeric α,β-tubulin to form a tight ternary complex called the
T2S complex.[7] One mole of stathmin binds to two moles of tubulin dimers through the
stathmin-like domain (SLD).[9] When stathmin sequesters tubulin into the T2S complex, tubulin becomes non-polymerizable. Without tubulin
polymerization, there is no microtubule assembly.[7] Stathmin also promotes microtubule disassembly by acting directly on the microtubule ends.[6]
The rate of microtubule assembly is an important aspect of cell growth therefore associating regulation of stathmin with
cell cycle progress. Regulation of stathmin is cell cycle dependent and controlled by the cell's
protein kinases in response to specific cell signals.[9]Phosphorylation at four serine residues on stathmin named
Ser16,
Ser25,
Ser38 and
Ser63 causes weakened stathmin-tubulin binding. Stathmin
phosphorylation increases the concentration of tubulin available in the cytoplasm for microtubule assembly. For cells to assemble the
mitotic spindle necessary for initiation of the mitotic phase of the cell cycle, stathmin phosphorylation must occur. Without microtubule growth and assembly, the mitotic spindle cannot form, and the cell cycle is arrested. At
cytokinesis, the last phase of the cell cycle, rapid dephosphorylation of stathmin occurs to block the cell from entering back into the cell cycle until it is ready.[9]
Clinical significance
Stathmin's role in regulation of the cell cycle causes it to be an
oncoprotein named
oncoprotein 18 (op18). Stathmin (aka op18) can cause uncontrolled cell proliferation when mutated and not functioning properly. If stathmin is unable to bind to tubulin, it allows for constant microtubule assembly and therefore constant
mitotic spindle assembly. With no regulation of the mitotic spindle, the cell cycle is capable of cycling uncontrollably resulting in the unregulated cell growth characteristic of
cancer cells.[9]
Role in social behaviour
Mice without stathmin have deficiency in innate and learned fear. Stathmin−/− females do not assess threats well, leading to lack of innate parental care and adult social interactions. They lack motivation for retrieving pups and are unable to choose a safe location for nest-building. However, they have an enhancement in social interactions.[13]
^
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abcdJourdain L, Curmi P, Sobel A, Pantaloni D, Carlier MF (September 1997). "Stathmin: a tubulin-sequestering protein which forms a ternary T2S complex with two tubulin molecules". Biochemistry. 36 (36): 10817–21.
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^Clément MJ, Jourdain I, Lachkar S, Savarin P, Gigant B, Knossow M, Toma F, Sobel A, Curmi PA (November 2005). "N-terminal stathmin-like peptides bind tubulin and impede microtubule assembly". Biochemistry. 44 (44): 14616–25.
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abcdeCassimeris L (February 2002). "The oncoprotein 18/stathmin family of microtubule destabilizers". Current Opinion in Cell Biology. 14 (1): 18–24.
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Sobel A (August 1991). "Stathmin: a relay phosphoprotein for multiple signal transduction?". Trends in Biochemical Sciences. 16 (8): 301–5.
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Steinmetz MO (May 2007). "Structure and thermodynamics of the tubulin-stathmin interaction". Journal of Structural Biology. 158 (2): 137–47.
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Kato S, Sekine S, Oh SW, Kim NS, Umezawa Y, Abe N, Yokoyama-Kobayashi M, Aoki T (December 1994). "Construction of a human full-length cDNA bank". Gene. 150 (2): 243–50.
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