stathmin

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.{{cite journal | vauthors = Kueh HY, Mitchison TJ | title = Structural plasticity in actin and tubulin polymer dynamics | journal = Science | volume = 325 | issue = 5943 | pages = 960–3 | date = August 2009 | pmid = 19696342 | pmc = 2864651 | doi = 10.1126/science.1168823 | bibcode = 2009Sci...325..960K }} More specifically, stathmin is crucial in regulating the cell cycle. It is found solely in eukaryotes.

Its function as an important regulatory protein of microtubule dynamics has been well-characterized.{{cite journal | vauthors = Jourdain L, Curmi P, Sobel A, Pantaloni D, Carlier MF | title = Stathmin: a tubulin-sequestering protein which forms a ternary T2S complex with two tubulin molecules | journal = Biochemistry | volume = 36 | issue = 36 | pages = 10817–21 | date = September 1997 | pmid = 9312271 | doi = 10.1021/bi971491b }} 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.{{cite journal | vauthors = Clément MJ, Jourdain I, Lachkar S, Savarin P, Gigant B, Knossow M, Toma F, Sobel A, Curmi PA | title = N-terminal stathmin-like peptides bind tubulin and impede microtubule assembly | journal = Biochemistry | volume = 44 | issue = 44 | pages = 14616–25 | date = November 2005 | pmid = 16262261 | doi = 10.1021/bi0512492 }}

At low concentrations of free tubulin, the growth rate at the microtubule ends is slowed and results in an increased rate of depolymerization (disassembly).{{cite journal | vauthors = Cassimeris L | title = The oncoprotein 18/stathmin family of microtubule destabilizers | journal = Current Opinion in Cell Biology | volume = 14 | issue = 1 | pages = 18–24 | date = February 2002 | pmid = 11792540 | doi = 10.1016/S0955-0674(01)00289-7 }}

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. Stathmin regulates these by promoting depolymerization of microtubules or preventing polymerization of tubulin heterodimers.{{cite journal | vauthors = Rubin CI, Atweh GF | title = The role of stathmin in the regulation of the cell cycle | journal = Journal of Cellular Biochemistry | volume = 93 | issue = 2 | pages = 242–50 | date = October 2004 | pmid = 15368352 | doi = 10.1002/jcb.20187 | s2cid = 406185 }}

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,{{cite journal | vauthors = Maucuer A, Doye V, Sobel A | title = A single amino acid difference distinguishes the human and the rat sequences of stathmin, a ubiquitous intracellular phosphoprotein associated with cell regulations | journal = FEBS Letters | volume = 264 | issue = 2 | pages = 275–8 | date = May 1990 | pmid = 2358074 | doi = 10.1016/0014-5793(90)80266-L | s2cid = 30922217 | doi-access = free | bibcode = 1990FEBSL.264..275M }} functioning through a variety of second messengers.

Its phosphorylation and gene expression are regulated throughout development{{cite journal | vauthors = Maucuer A, Moreau J, Méchali M, Sobel A | title = Stathmin gene family: phylogenetic conservation and developmental regulation in Xenopus | journal = The Journal of Biological Chemistry | volume = 268 | issue = 22 | pages = 16420–9 | date = August 1993 | doi = 10.1016/S0021-9258(19)85437-6 | pmid = 8344928 | doi-access = free }} and in response to extracellular signals regulating cell proliferation, differentiation and function.{{cite journal | vauthors = Doye V, Soubrier F, Bauw G, Boutterin MC, Beretta L, Koppel J, Vandekerckhove J, Sobel A | title = A single cDNA encodes two isoforms of stathmin, a developmentally regulated neuron-enriched phosphoprotein | journal = The Journal of Biological Chemistry | volume = 264 | issue = 21 | pages = 12134–7 | date = July 1989 | doi = 10.1016/S0021-9258(18)63830-X | pmid = 2745432 | doi-access = free }}

Interactions

{{Infobox protein family

| Symbol = Stathmin

| Name = Stathmin

| image = PDB 1z2b EBI.jpg

| width =

| caption = Structure of Tubulin-Colchicine-Vinblastine: Stathmin-like domain complex

| Pfam = PF00836

| Pfam_clan =

| InterPro = IPR000956

| SMART =

| PROSITE = PDOC00487

| MEROPS =

| SCOP = 1sa0

| TCDB =

| OPM family =

| OPM protein =

| CAZy =

| CDD =

}}

Stathmin interacts with two molecules of dimeric α,β-tubulin to form a tight ternary complex called the T2S complex. One mole of stathmin binds to two moles of tubulin dimers through the stathmin-like domain (SLD). When stathmin sequesters tubulin into the T2S complex, tubulin becomes non-polymerizable. Without tubulin polymerization, there is no microtubule assembly. Stathmin also promotes microtubule disassembly by acting directly on the microtubule ends.

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. 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.

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.

References

External links

[https://www.nlm.nih.gov/cgi/mesh/2008/MB_cgi NLM]
[http://www.stathmin.com/ Stathmin.com]

Category:Cell cycle regulators

Category:Human proteins

Category:Protein families

Category:Cytoskeleton