Gelsolin is an
actin-binding protein that is a key regulator of actin filament assembly and disassembly. Gelsolin is one of the most potent members of the actin-severing gelsolin/ villinsuperfamily, as it severs with nearly 100% efficiency.cite journal |author=Sun, H., Yamamoto, M., Mejillano, M., Yin, H. |title=Gelsolin, a Multifunction Actin Regulatory Protein |journal=J Biol Chem |year=1999 |volume=274 |issue=47 |pages=33179–33182 |doi=10.1074/jbc.274.47.33179 ] Gelsolin is located intracellularly (in cytosoland mitochondria) and extracellularly (in blood plasma).cite journal |author=Koya, R., Fujita, H., Shimizu, S., Ohtsu, M., Takimoto, M., Tsujimoto, Y., Kuzumaki, N. |title=Gelsolin Inhibits Apoptosis by Blocking Mitochondrial Membrane Potential Loss and Cytochrome C Release |journal=J Biol Chem |year=2000 |volume=275 |issue=20 |pages=15343–15349 |url=http://www.jbc.org/cgi/content/full/275/20/15343 |pmid=10809769 |doi=10.1074/jbc.275.20.15343]
Gelsolin is an 82-kD protein with six homologous subdomains, referred to as S1-S6. Each subdomain is composed of a five-stranded
β-sheet, flanked by two α-helices, one positioned perpendicular with respect to the strands and one positioned parallel. The N-terminal(S1-S3) forms an extended β-sheet, as does the C-terminal(S4-S6).cite journal |author=Kiselar, J., Janmey, P., Almo, S., Chance, M. |title=Visualizing the Ca2+-dependent activation of gelsolin by using synchrotron footprinting |journal=PNAS |year=2003 |volume=100 |issue=7 |pages=3942–3947 |url=http://www.pnas.org/cgi/content/full/100/7/3942 |pmid=12655044 |doi=10.1073/pnas.0736004100]
lipidbinding actin regulatory proteins, gelsolin (along with cofilin) is one of the few that exhibit preferential binding towards polyphosphoinositide (PPIs).cite journal |author=Yu, F., Sun, H., Janmey, P., Yin, H. |title=Identification of a Polyphosphoinositide-binding Sequence in an Actin Monomer-binding Domain of Gelsolin |journal=J Biol Chem |year=1992 |volume=267 |issue=21 |pages=14616–14621 |url=http://www.jbc.org/cgi/reprint/267/21/14616.pdf |pmid=1321812] The binding sequences in gelsolin closely resemble the motifs in the other PPI-binding proteins.
Gelsolin's activity is stimulated by calcium ions (Ca2+). Although the protein retains its overall structural integrity in both activated and deactivated states, the S6 helical tail moves like a latch depending on the concentration of calcium ions.cite journal |author=Burtnick, L, Urosev, D., Irobi, E., Narayan, K., Robinson, R. |title=Structure of the N-terminal half of gelsolin bound to actin: roles in severing, apoptosis and FAF |journal=The EMBO Journal |year=2004 |volume=23 |pages=2713–2722 |url=http://www.nature.com/emboj/journal/v23/n14/full/7600280a.html |pmid=15215896 |doi=10.1038/sj.emboj.7600280] The C-terminal end detects the calcium concentration within the cell. When there is no Ca2+ present, the tail of S6 shields the actin-binding sites on one of S2's helices. When a calcium ion attaches to the S6 tail, however, it straightens, exposing the S2 actin-binding sites. The N-terminal is directly involved in the severing of actin. S2 and S3 bind to the actin before the binding of S1 severs actin-actin bonds and caps the barbed end.
Gelsolin can be inhibited by a local rise in the concentration of
phosphatidylinositol (4,5)-bisphosphate(PIP2), a PPI. This is a two step process. Firstly, (PIP2) binds to S2 and S3, inhibiting gelsolin from actin side binding. Then, (PIP2) binds to gelsolin’s S1, preventing gelsolin from severing actin, although (PIP2) does not bind directly to gelsolin's actin-binding site.
Gelsolin's severing of actin, in contrast to the severing of
microtubulesby katanin, does not require any extra energy input.
As an important actin regulator, gelsolin plays a role in
podosomeformation (along with Arp3, cortactin, and Rho GTPases).cite journal |author=Varon, C., Tatin, F., Moreau, V., Obberghen-Schilling, E., Fernandez-Sauze, S., Reuzeau, E., Kramer, I., Génot, E. |title=Transforming Growth Factor β Induces Rosettes of Podosomes in Primary Aortic Endothelial Cells |journal=Molecular and Cellular Biology |year=2005 |volume=26 |issue=9 |pages=3582–3594 |url=http://mcb.asm.org/cgi/content/full/26/9/3582 |pmid=16611998 |doi=10.1128/MCB.26.9.3582-3594.2006]
Gelsolin also inhibits
apoptosisby stabilizing the mitochondria. Prior to cell death, mitochondria normally lose membrane potentialand become more permeable. Gelsolin can impede the release of cytochrome C, obstructing the signal amplification that would have led to apoptosis.
Actin can be cross-linked into a
gelby actin cross-linking proteins. Gelsolin can turn this gel into a sol, hence the name gelsolin.
Research in mice suggests that gelsolin, like other actin-severing proteins, is not expressed to a significant degree until after the early
embryonic stage--approximately 2 weeks in murineembryos.cite journal |author=Witke, W., Sharpe, A., Hartwig, J., Azuma, T., Stossel, T., Kwiatkowski, D. |title=Hemostatic, Inflammatory, and Fibroblast Responses Are Blunted in Mice Lacking Gelsolin |journal=Cell |year=1995 |volume=81 |pages=41–51 |url=http://www.cell.com/content/article/abstract?uid=PII0092867495903690&session= |pmid=7720072 |doi=10.1016/0092-8674(95)90369-0] In adult specimens, however, gelsolin is particularly important in motile cells, such as blood platelets. Mice with null gelsolin-coding genesundergo normal embryonic development, but the deformation of their blood platelets reduced their motility, resulting in a slower response to wound healing.
An insufficiency of gelsolin in mice has also been shown to cause increased permeability of the vascular pulmonary barrier, suggesting that gelsolin is important in the response to lung injury.cite journal |author=Becker, P., Kazi, A., Wadgaonkar, R., Pearse, D., Kwiatkowski, D., Garcia, J. |title=Pulmonary Vascular Permeability and Ischemic Injury in Gelsolin-Deficient Mice |journal=American Journal of Respiratory Cell and Molecular Biology |year=2003 |volume=28 |pages=478–484 |url=http://ajrcmb.atsjournals.org/cgi/content/full/28/4/478 |pmid=12654637 |doi=10.1165/rcmb.2002-0024OC]
Finnish type amyloidosis
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