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/villin superfamily, as it severs with nearly 100% efficiency.^[1] Gelsolin is located intracellularly (in cytosol and mitochondria) and extracellularly (in blood plasma).^[2] Hugo is a masculine name. ... The Entrez logo The Entrez Global Query Cross-Database Search System allows access to databases at the National Center for Biotechnology Information (NCBI) website. ... The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ... The National Center for Biotechnology Information (NCBI) is part of the US National Library of Medicine (NLM), which is a branch of the US National Institutes of Health. ... Swiss-Prot is a curated biological database of protein sequences created in 1986 by Amos Bairoch during his PhD and developed by the Swiss Institute of Bioinformatics and the European Bioinformatics Institute. ... Short and long arms Chromosome. ... Chromosome 9 is one of the 23 pairs of chromosomes in humans. ... G-Actin (PDB code: 1j6z). ... Villin is an actin-binding protein that contains gelsolin domains capped by a headpiece consisting of a fast- and independently-folding three-helix bundle that is stabilized by hydrophobic interactions. ... The cytosol (cf. ... In cell biology, a mitochondrion is an organelle found in the cells of most eukaryotes. ... Blood plasma is the liquid component of blood, in which the blood cells are suspended. ...

Structure

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).^[3] Diagram of β-pleated sheet with H-bonding between protein strands The β sheet (also β-pleated sheet) is the second form of regular secondary structure in proteins — the first is the alpha helix — consisting of beta strands connected laterally by three or more hydrogen bonds, forming a generally twisted, pleated sheet. ... Side view of an α-helix of alanine residues in atomic detail. ... The N-terminal end refers to the extremity of a protein or polypeptide terminated by an amino acid with a free amine group (NH2). ... The C-terminal end refers to the extremity of a protein or polypeptide terminated by an amino acid with a free carboxyl group (COOH). ...

Regulation

Among the lipid binding actin regulatory proteins, gelsolin (along with cofilin) is one of the few that exhibit preferential binding towards polyphosphoinositide (PPIs).^[4] The binding sequences in gelsolin closely resemble the motifs in the other PPI-binding proteins.^[4] A polyunsaturated triglyceride. ... ADF/cofilin is a family of actin-binding proteins that disassembles actin filaments. ...

Gelsolin's activity is stimulated by calcium ions (Ca2+).^[1] 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.^[5] 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.^[3] When a calcium ion attaches to the S6 tail, however, it straightens, exposing the S2 actin-binding sites.^[5] 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.^[4]

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.^[4] Chemical structure of sn-1-stearoyl-2-arachidonoyl phosphatidylinositol 4,5-bisphosphate Phosphatidylinositol (4,5)-bisphosphate (PtdIns(4,5)P2) is a minor phospholipid component of cell membranes. ...

Gelsolin's severing of actin, in contrast to the severing of microtubules by katanin, does not require any extra energy input. Microtubules are protein structures found within cells. ... // Katanin is an AAA adenosine triphosphatase microtubule severing protein named for the Japanese’s word for sword (Katana). ...

Cellular Function

As an important actin regulator, gelsolin plays a role in podosome formation (along with Arp3, cortactin, and Rho GTPases).^[6] Podosomes are the primary sites of integrin stimulated actin polymerization in leukocytes of the monocytic lineage. ...

Gelsolin also inhibits apoptosis by stabilizing the mitochondria ^[2]. Prior to cell death, mitochondria normally lose membrane potential and become more permeable. Gelsolin can impede the release of cytochrome C, obstructing the signal amplification that would have led to apoptosis. A cell undergoing apoptosis. ... In cell biology, a mitochondrion is an organelle found in the cells of most eukaryotes. ... This article or section is in need of attention from an expert on the subject. ... Cytochrome c with heme c. ...

Organismal Relevance

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 murine embryos.^[7] In adult specimens, however, gelsolin is particularly important in motile cells, such as blood platelets. Mice with null gelsolin-coding genes undergo normal embryonic development, but the deformation of their blood platelets reduced their motility, resulting in a slower response to wound healing.^[7] It has been suggested that embryology be merged into this article or section. ... Species 50 species; see text *Several subfamilies of Muroids include animals called rats. ... A 250 ml bag of newly collected platelets. ... This stylistic schematic diagram shows a gene in relation to the double helix structure of DNA and to a chromosome (right). ... Embryogenesis is the process by which the embryo is formed and develops. ...

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.^[8]

References

1. ^ ^{a b} Sun, H., Yamamoto, M., Mejillano, M., Yin, H. (1999). "Gelsolin, a Multifunction Actin Regulatory Protein". J Biol Chem 274 (47): 33179–33182. 
2. ^ ^{a b} Koya, R., Fujita, H., Shimizu, S., Ohtsu, M., Takimoto, M., Tsujimoto, Y., Kuzumaki, N. (2000). "Gelsolin Inhibits Apoptosis by Blocking Mitochondrial Membrane Potential Loss and Cytochrome C Release". J Biol Chem 275 (20): 15343-15349. PMID 10809769. 
3. ^ ^{a b} Kiselar, J., Janmey, P., Almo, S., Chance, M. (2003). "Visualizing the Ca2+-dependent activation of gelsolin by using synchrotron footprinting". PNAS 100 (7): 3942-3947. PMID 12655044. 
4. ^ ^{a b c d} Yu, F., Sun, H., Janmey, P., Yin, H. (1992). "Identification of a Polyphosphoinositide-binding Sequence in an Actin Monomer-binding Domain of Gelsolin". J Biol Chem 267 (21): 14616-14621. PMID 1321812. 
5. ^ ^{a b} Burtnick, L, Urosev, D., Irobi, E., Narayan, K., Robinson, R. (2004). "Structure of the N-terminal half of gelsolin bound to actin: roles in severing, apoptosis and FAF". The EMBO Journal 23: 2713–2722. PMID 15215896. 
6. ^ Varon, C., Tatin, F., Moreau, V., Obberghen-Schilling, E., Fernandez-Sauze, S., Reuzeau, E., Kramer, I., Génot, E. (2005). "Transforming Growth Factor ß Induces Rosettes of Podosomes in Primary Aortic Endothelial Cells". Molecular and Cellular Biology 26 (9): 3582-3594. PMID 16611998. 
7. ^ ^{a b} Witke, W., Sharpe, A., Hartwig, J., Azuma, T., Stossel, T., Kwiatkowski, D. (1995). "Hemostatic, Inflammatory, and Fibroblast Responses Are Blunted in Mice Lacking Gelsolin". Cell 81: 41-51. PMID 7720072. 
8. ^ Becker, P., Kazi, A., Wadgaonkar, R., Pearse, D., Kwiatkowski, D., Garcia, J. (2003). "Pulmonary Vascular Permeability and Ischemic Injury in Gelsolin-Deficient Mice". American Journal of Respiratory Cell and Molecular Biology 28: 478-484. PMID 12654637. 

See Also

• Cortactin
• Villin

Villin is an actin-binding protein that contains gelsolin domains capped by a headpiece consisting of a fast- and independently-folding three-helix bundle that is stabilized by hydrophobic interactions. ...

External links

• MeSH Gelsolin