User:Alisa Cario
From Proteopedia
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[[Image:Stathmin_figure_cario1.png|center|thumb| upright=3| Figure XXX. Stathmin in purple can bind to tubulin dimers to prevent polymerization or to microtubules to increase catastrophe ]] | [[Image:Stathmin_figure_cario1.png|center|thumb| upright=3| Figure XXX. Stathmin in purple can bind to tubulin dimers to prevent polymerization or to microtubules to increase catastrophe ]] | ||
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== '''Function''' == | == '''Function''' == | ||
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'''Mitosis''': Stathmin's role in the cell cycle progression is well characterized. During interphase, microtubules are relatively stable. However during the onset of mitosis, stathmin is upregulated to increase the rate of catastrophe of microtubules, causing them to become more dynamic. Stathmin has also been shown to bind and sequester two tubulin heterodimers, reducing the amount of available tubulin to polymerize microtubules <ref>PMID:9312271</ref>. However, as mitosis progresses, microtubules must repolymerize to form the mitotic spindle. Stathmin is regulated during this process by phosphorylation <ref>PMID: 7982983</ref> <ref>PMID: 1737801</ref>. There are four known <scene name='77/778894/Stathmin_phospho/1'>phosphorylation sites of stathmin</scene>, serine 16, serine 25, serine 38, and serine 63 <ref>PMID: 8376365</ref>. Stathmin is the known target of cyclin-dependent kinases <ref>PMID: 9271428 </ref>. Stathmin overexpression prevents mitotic spindle formation where inhibition interferes with later stages in mitosis <ref> </ref>. | '''Mitosis''': Stathmin's role in the cell cycle progression is well characterized. During interphase, microtubules are relatively stable. However during the onset of mitosis, stathmin is upregulated to increase the rate of catastrophe of microtubules, causing them to become more dynamic. Stathmin has also been shown to bind and sequester two tubulin heterodimers, reducing the amount of available tubulin to polymerize microtubules <ref>PMID:9312271</ref>. However, as mitosis progresses, microtubules must repolymerize to form the mitotic spindle. Stathmin is regulated during this process by phosphorylation <ref>PMID: 7982983</ref> <ref>PMID: 1737801</ref>. There are four known <scene name='77/778894/Stathmin_phospho/1'>phosphorylation sites of stathmin</scene>, serine 16, serine 25, serine 38, and serine 63 <ref>PMID: 8376365</ref>. Stathmin is the known target of cyclin-dependent kinases <ref>PMID: 9271428 </ref>. Stathmin overexpression prevents mitotic spindle formation where inhibition interferes with later stages in mitosis <ref> </ref>. | ||
| - | '''Migration''': The cytoskeleton is a vital part of cell migration. The leading edge is driven by actin polymerization ( ). However, microtubules are needed to retract from the trailing edge to move the cell forward. Stathmin is thought to have a role in migration, allowing to microtubules to depolymerize to aid in movement. Stathmin has been show to be a part of the integrin alpha5 beta1/FAK/ ERK pathway | + | '''Migration''': The cytoskeleton is a vital part of cell migration. The leading edge is driven by actin polymerization ( ). However, microtubules are needed to retract from the trailing edge to move the cell forward. Stathmin is thought to have a role in migration, allowing to microtubules to depolymerize to aid in movement. Stathmin has been show to be a part of the integrin alpha5 beta1/FAK/ ERK pathway <ref>PMID: 9462839</ref>. |
| - | '''Differentiation''': Stathmin expression is regulated during stages of development. It is regulated in early and late embryogenesis. ( | + | '''Differentiation''': Stathmin expression is regulated during stages of development. It is regulated in early and late embryogenesis. ( <ref></ref> ) . It is also regulated in differentiating muscle cells, T lymphocytes, and oligodendryocytes (<ref></ref>). |
== '''Structural Highlights''' == | == '''Structural Highlights''' == | ||
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<scene name='77/778894/Stathmin_alone/1'>Stathmin</scene> consistis of a coiled coil alpha helix, that binds across two tubulin heterodimers, and a mostly disordered N-terminal region that also has some beta strand properties. These different regions of the protein are known to have different functions. | <scene name='77/778894/Stathmin_alone/1'>Stathmin</scene> consistis of a coiled coil alpha helix, that binds across two tubulin heterodimers, and a mostly disordered N-terminal region that also has some beta strand properties. These different regions of the protein are known to have different functions. | ||
| - | The <scene name='77/778894/Stathmin_nterm/1'>N-terminal region</scene> is known to increase tubulin catastrophe. This region helps destabilize the ends of the microtubule filaments by curving the tubulin dimers at the end, and disrupting lateral hydrogen bonds. The N-terminal region is known as the regulatory domain of the protein, because it is subject to most of the post-translational modifications | + | The <scene name='77/778894/Stathmin_nterm/1'>N-terminal region</scene> is known to increase tubulin catastrophe. This region helps destabilize the ends of the microtubule filaments by curving the tubulin dimers at the end, and disrupting lateral hydrogen bonds. The N-terminal region is known as the regulatory domain of the protein, because it is subject to most of the post-translational modifications. This region binds and caps alpha tubulin to accomplish this task. (<ref></ref>) |
| - | The<scene name='77/778894/Stathmin_c_term/1'> C-terminal region</scene>, also known as the interaction domain, is known to sequester tubulin heterodimers. This region is comprised of a <scene name='77/778894/Stathmin_coiled_coil/1'>coiled-coil alpha helix</scene>. This region of stathmin is <scene name='77/778894/Zoom_of_stathmin_on_alpha/1'>known to bind to helix 10 of alpha tubulin</scene>. Helix 10 of alpha tubulin is thought to be important for incorporation into microtubules ( ) . | + | The<scene name='77/778894/Stathmin_c_term/1'> C-terminal region</scene>, also known as the interaction domain, is known to sequester tubulin heterodimers. This region is comprised of a <scene name='77/778894/Stathmin_coiled_coil/1'>coiled-coil alpha helix</scene>. This region of stathmin is <scene name='77/778894/Zoom_of_stathmin_on_alpha/1'>known to bind to helix 10 of alpha tubulin</scene>. Helix 10 of alpha tubulin is thought to be important for incorporation into microtubules (<ref></ref>). |
| - | The structure of stathmin, in 4eb6, is bound to two tubulin heterodimers. The tubulin dimers are bound to outside ligands. <scene name='77/778894/Vinblastine/1'>Vinblastine</scene> is a chemotherapeutic that binds to tubulin to prevent microtubule polymerization ( | + | The structure of stathmin, in 4eb6, is bound to two tubulin heterodimers. The tubulin dimers are bound to outside ligands. <scene name='77/778894/Vinblastine/1'>Vinblastine</scene> is a chemotherapeutic that binds to tubulin to prevent microtubule polymerization ( <ref></ref>). The tubulin subunits are bound to from <scene name='77/778894/Gtp_gdp_highlight_of_tubulin/1'>GTP/GDP.</scene> The beta subunits of tubulin are bound to GDP and each of the alpha subunits are bound to GTP and a Magnesium ion. There are also <scene name='77/778894/Mutations_in_stathmin/1'>two mutations</scene> to the stathmin in this structure. The mutations at position 11 from an cysteine to an alanine and position 16 from a Phenylalanine to a Tryptophan. |
== '''Disease relevance''' == | == '''Disease relevance''' == | ||
| - | '''Multiple Schlerosis''': Stathmin expression is has been linked to multiple sclerosis (MS) , a neurodegenerative disorder characterized by lack of motor control and numbness. MS is caused by loss of myelination on axons in the nervous system. Myelination of axons is performed by cells called oligodendrocytes. Stathmin is regulated in oligodendrocyte lineage, with progenitor cells containing larger amounts than differentiated oligodendrocytes. Brain tissue samples from people suffering from multiple sclerosis found that stathmin is up regulated later in the lineage of oligodendrocytes. The up-regulation of stathmin showed a more globular morphology of the cells. Oligodendrocyte ability to myelinate axons in the central nervous system was greatly reduced in these patients ( | + | '''Multiple Schlerosis''': Stathmin expression is has been linked to multiple sclerosis (MS) , a neurodegenerative disorder characterized by lack of motor control and numbness. MS is caused by loss of myelination on axons in the nervous system. Myelination of axons is performed by cells called oligodendrocytes. Stathmin is regulated in oligodendrocyte lineage, with progenitor cells containing larger amounts than differentiated oligodendrocytes. Brain tissue samples from people suffering from multiple sclerosis found that stathmin is up regulated later in the lineage of oligodendrocytes. The up-regulation of stathmin showed a more globular morphology of the cells. Oligodendrocyte ability to myelinate axons in the central nervous system was greatly reduced in these patients (. <ref></ref>). |
| - | '''Cancer''': Due to stathmin's role in mitosis and cell migration, it is not surprising that is has been implicated in many cancers and is an active target of cancer therapeutics. Stathmin is defined as an oncoprotein. Overexpression of stathmin has been shown to increase metastasis, worse prognosis, and increased chemoresistance ( | + | '''Cancer''': Due to stathmin's role in mitosis and cell migration, it is not surprising that is has been implicated in many cancers and is an active target of cancer therapeutics. Stathmin is defined as an oncoprotein. Overexpression of stathmin has been shown to increase metastasis, worse prognosis, and increased chemoresistance ( <ref></ref> ). Stathmin levels are known to be increasesd in a number of cancers. Stathmin was seen to be upregulated in breast cancer tissue comparative with normal breast tissue ( <ref></ref>). Another study was done to show stathmin upregulation in esophageal squamous cell carcinomas (<ref></ref> ). Studies using a non-phosphorylatable stathmin mutant shows that cells arrest during mitosis (Marklund, Larson<ref></ref>) |
== '''Evolutionary conservation''' == | == '''Evolutionary conservation''' == | ||
| - | Stathmin belongs to a gene family that have a characteristic stathmin-like domain. There are four isoforms of stathmin which are alternatively spliced from a single gene. This family includes Stathmin-1, SCG10/stathmin-2, SCILP/stathmin-3, and RB3/stathmin-4. SCG10 and SCLIP, are exclusively neuronal proteins, while RB3 is expressed mostly in the brain but some in the adrenal glands. Unlike the neuronal proteins, stathmin-1 is ubiquitously expressed in all cell types. All members of this family contain the C-terminal coiled coil domain. However, the binding affinity to tubulin of the protein family members differ (. | + | Stathmin belongs to a gene family that have a characteristic stathmin-like domain. There are four isoforms of stathmin which are alternatively spliced from a single gene. This family includes Stathmin-1, SCG10/stathmin-2, SCILP/stathmin-3, and RB3/stathmin-4. SCG10 and SCLIP, are exclusively neuronal proteins, while RB3 is expressed mostly in the brain but some in the adrenal glands. Unlike the neuronal proteins, stathmin-1 is ubiquitously expressed in all cell types. All members of this family contain the C-terminal coiled coil domain. However, the binding affinity to tubulin of the protein family members differ (. <ref></ref> ). Interestingly, the neuronal isoforms are known to contain an additional N-terminal domain to affect their localization ( <ref></ref> ). |
== Links to available structures == | == Links to available structures == | ||
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LarssonN,MarklundU,GradinHM,BrattsandGandGullbergM (1997)Controlof microtubule dynamics by oncoprotein 18: dissection of the regulatory role of multisite phosphorylation during mitosis. Mol Cell Biol 17: 553(-5539 | LarssonN,MarklundU,GradinHM,BrattsandGandGullbergM (1997)Controlof microtubule dynamics by oncoprotein 18: dissection of the regulatory role of multisite phosphorylation during mitosis. Mol Cell Biol 17: 553(-5539 | ||
| - | Lawler S, Gavet 0, Rich T and Sobel A (1998) Stathmin overexpression in 293 cells | + | Lawler S, Gavet 0, Rich T and Sobel A (1998) Stathmin overexpression in 293 cells affects signaltransductionandthecelcycle.FEBS Lett421:55-60 |
StrahlerJR,LambBJ,UngarDR,FoxDA andHanashSM (1992)Cellcycle progressionisassociatedwithdistinctpatternsofphosphorylationofOp18. BiochemBiophvsResCommun 185:197-203 | StrahlerJR,LambBJ,UngarDR,FoxDA andHanashSM (1992)Cellcycle progressionisassociatedwithdistinctpatternsofphosphorylationofOp18. BiochemBiophvsResCommun 185:197-203 | ||
Revision as of 22:44, 27 April 2018
* Full Real Name: Alisa Cario
- Position: Graduate Student
- Institution (NO ABBREVIATIONS): University of Vermont
- City, State/Province, Country: Burlington, VT USA
- Field of Expertise or Study: Creation of protopedia page for a class project. The class is Proteins 1 under Dr. Stephen Everse
Stathmin-4 (RB3) bound to Tubulin stabilized with Vinblastin
4eb6
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