Biology:Stathmin
 Generic protein structure example |
Stathmin, also known as metablastin and oncoprotein 18 is a protein that in humans is encoded by the STMN1 gene.
Stathmin is a highly conserved 17 kDa protein 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.[1] More specifically, stathmin is crucial in regulating the cell cycle.[2] It is found solely in eukaryotes.
Its function as an important regulatory protein of microtubule dynamics has been well-characterized.[3] 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.[4]
At low concentrations of free tubulin, the growth rate at the microtubule ends is slowed and results in an increased rate of depolymerization (disassembly).[3][5]
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 acid coiled-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 tubulin heterodimers. The changes in cytoskeleton are known as microtubule dynamics; the addition of the tubulin subunits lead to polymerisation and their loss, depolymerisation.[1] Stathmin regulates these by promoting depolymerization of microtubules or preventing polymerization of tubulin heterodimers.[2]
Additionally, Stathmin is thought to have a role in cell signaling pathway. Stathmin is a ubiquitous phosphorylated protein which makes it act as an intracellular relay for diverse regulatory pathways,[6] functioning through a variety of second messengers.
Its phosphorylation and gene expression are regulated throughout development[7] and in response to extracellular signals regulating cell proliferation, differentiation and function.[8]
Interactions
| Stathmin | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 Structure of Tubulin-Colchicine-Vinblastine: Stathmin-like domain complex | |||||||||
| Identifiers | |||||||||
| Symbol | Stathmin | ||||||||
| Pfam | PF00836 | ||||||||
| InterPro | IPR000956 | ||||||||
| PROSITE | PDOC00487 | ||||||||
| SCOP2 | 1sa0 / SCOPe / SUPFAM | ||||||||
| |||||||||
Stathmin interacts with two molecules of dimeric α,β-tubulin to form a tight ternary complex called the T2S complex.[3] One mole of stathmin binds to two moles of tubulin dimers through the stathmin-like domain (SLD).[5] When stathmin sequesters tubulin into the T2S complex, tubulin becomes non-polymerizable. Without tubulin polymerization, there is no microtubule assembly.[3] Stathmin also promotes microtubule disassembly by acting directly on the microtubule ends.[2]
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.[5] 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.[5]
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.[5]
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.[9]
References
- ↑ 1.0 1.1 "Structural plasticity in actin and tubulin polymer dynamics". Science 325 (5943): 960–3. August 2009. doi:10.1126/science.1168823. PMID 19696342. Bibcode: 2009Sci...325..960K.
- ↑ 2.0 2.1 2.2 "The role of stathmin in the regulation of the cell cycle". Journal of Cellular Biochemistry 93 (2): 242–50. October 2004. doi:10.1002/jcb.20187. PMID 15368352.
- ↑ 3.0 3.1 3.2 3.3 "Stathmin: a tubulin-sequestering protein which forms a ternary T2S complex with two tubulin molecules". Biochemistry 36 (36): 10817–21. September 1997. doi:10.1021/bi971491b. PMID 9312271.
- ↑ "N-terminal stathmin-like peptides bind tubulin and impede microtubule assembly". Biochemistry 44 (44): 14616–25. November 2005. doi:10.1021/bi0512492. PMID 16262261.
- ↑ 5.0 5.1 5.2 5.3 5.4 "The oncoprotein 18/stathmin family of microtubule destabilizers". Current Opinion in Cell Biology 14 (1): 18–24. February 2002. doi:10.1016/S0955-0674(01)00289-7. PMID 11792540.
- ↑ "A single amino acid difference distinguishes the human and the rat sequences of stathmin, a ubiquitous intracellular phosphoprotein associated with cell regulations". FEBS Letters 264 (2): 275–8. May 1990. doi:10.1016/0014-5793(90)80266-L. PMID 2358074.
- ↑ "Stathmin gene family: phylogenetic conservation and developmental regulation in Xenopus". The Journal of Biological Chemistry 268 (22): 16420–9. August 1993. doi:10.1016/S0021-9258(19)85437-6. PMID 8344928.
- ↑ "A single cDNA encodes two isoforms of stathmin, a developmentally regulated neuron-enriched phosphoprotein". The Journal of Biological Chemistry 264 (21): 12134–7. July 1989. doi:10.1016/S0021-9258(18)63830-X. PMID 2745432.
- ↑ "Stathmin reveals dissociable roles of the basolateral amygdala in parental and social behaviors". Proceedings of the National Academy of Sciences of the United States of America 105 (38): 14620–5. September 2008. doi:10.1073/pnas.0807507105. PMID 18794533. Bibcode: 2008PNAS..10514620M.
Further reading
- "Stathmin: a relay phosphoprotein for multiple signal transduction?". Trends in Biochemical Sciences 16 (8): 301–5. August 1991. doi:10.1016/0968-0004(91)90123-D. PMID 1957351.
- "Structure and thermodynamics of the tubulin-stathmin interaction". Journal of Structural Biology 158 (2): 137–47. May 2007. doi:10.1016/j.jsb.2006.07.018. PMID 17029844.
- "Expression of transfected stathmin cDNA reveals novel phosphorylated forms associated with developmental and functional cell regulation". The Biochemical Journal 287 ( Pt 2) (Pt 2): 549–54. October 1992. doi:10.1042/bj2870549. PMID 1445213.
- "Analysis of phosphoprotein p19 by liquid chromatography/mass spectrometry. Identification of two proline-directed serine phosphorylation sites and a blocked amino terminus". The Journal of Biological Chemistry 267 (5): 3506–13. February 1992. doi:10.1016/S0021-9258(19)50759-1. PMID 1737801.
- "Characterization of the gene for a proliferation-related phosphoprotein (oncoprotein 18) expressed in high amounts in acute leukemia". The Journal of Biological Chemistry 266 (27): 17747–53. September 1991. doi:10.1016/S0021-9258(18)55189-9. PMID 1917919.
- "A gene that encodes for a leukemia-associated phosphoprotein (p18) maps to chromosome bands 1p35-36.1". Genes, Chromosomes & Cancer 2 (2): 125–9. July 1990. doi:10.1002/gcc.2870020208. PMID 2278968.
- "A single amino acid difference distinguishes the human and the rat sequences of stathmin, a ubiquitous intracellular phosphoprotein associated with cell regulations". FEBS Letters 264 (2): 275–8. May 1990. doi:10.1016/0014-5793(90)80266-L. PMID 2358074.
- "Molecular cloning of a novel human leukemia-associated gene. Evidence of conservation in animal species". The Journal of Biological Chemistry 264 (24): 14556–60. August 1989. doi:10.1016/S0021-9258(18)71714-6. PMID 2760073.
- "Intracellular substrates for extracellular signaling. Characterization of a ubiquitous, neuron-enriched phosphoprotein (stathmin)". The Journal of Biological Chemistry 264 (7): 3765–72. March 1989. doi:10.1016/S0021-9258(19)84915-3. PMID 2917975.
- "Stathmin interaction with a putative kinase and coiled-coil-forming protein domains". Proceedings of the National Academy of Sciences of the United States of America 92 (8): 3100–4. April 1995. doi:10.1073/pnas.92.8.3100. PMID 7724523. Bibcode: 1995PNAS...92.3100M.
- "Construction of a human full-length cDNA bank". Gene 150 (2): 243–50. December 1994. doi:10.1016/0378-1119(94)90433-2. PMID 7821789.
- "Molecular characterization of human stathmin expressed in Escherichia coli: site-directed mutagenesis of two phosphorylatable serines (Ser-25 and Ser-63)". The Biochemical Journal 300 ( Pt 2) (Pt 2): 331–8. June 1994. doi:10.1042/bj3000331. PMID 8002936.
- "Human and rat osteoblast-like cells express stathmin, a growth-regulatory protein". Biochemical and Biophysical Research Communications 201 (2): 861–5. June 1994. doi:10.1006/bbrc.1994.1780. PMID 8003023.
- "Cell-cycle-regulated phosphorylation of oncoprotein 18 on Ser16, Ser25 and Ser38". European Journal of Biochemistry 220 (2): 359–68. March 1994. doi:10.1111/j.1432-1033.1994.tb18632.x. PMID 8125092.
- "Multiple signal transduction pathways induce phosphorylation of serines 16, 25, and 38 of oncoprotein 18 in T lymphocytes". The Journal of Biological Chemistry 268 (34): 25671–80. December 1993. doi:10.1016/S0021-9258(19)74442-1. PMID 8245003.
- "Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase". The Journal of Biological Chemistry 268 (20): 15039–47. July 1993. doi:10.1016/S0021-9258(18)82435-8. PMID 8325880.
- "Multiple phosphorylation of stathmin. Identification of four sites phosphorylated in intact cells and in vitro by cyclic AMP-dependent protein kinase and p34cdc2". The Journal of Biological Chemistry 268 (27): 20076–84. September 1993. doi:10.1016/S0021-9258(20)80696-6. PMID 8376365.
- "Transcriptional and post-transcriptional regulation of pr22 (Op18) with proliferation control". Cell Structure and Function 21 (4): 237–43. August 1996. doi:10.1247/csf.21.237. PMID 8906359.
- "Control of microtubule dynamics by oncoprotein 18: dissection of the regulatory role of multisite phosphorylation during mitosis". Molecular and Cellular Biology 17 (9): 5530–9. September 1997. doi:10.1128/mcb.17.9.5530. PMID 9271428.
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