# Gelsolin

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{{Short description|Mammalian protein found in Homo sapiens}}
{{Infobox gene}}
'''Gelsolin''' is an [actin](/source/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](/source/villin) superfamily, as it severs with nearly 100% efficiency.<ref name="pmid24155256">{{cite journal | vauthors = Ghoshdastider U, Popp D, Burtnick LD, Robinson RC | title = The expanding superfamily of gelsolin homology domain proteins | journal = Cytoskeleton | volume = 70 | issue = 11 | pages = 775–95 | date = November 2013 | pmid = 24155256 | doi = 10.1002/cm.21149 | s2cid = 205643538 }}</ref><ref name="Sun">{{cite journal | vauthors = Sun HQ, Yamamoto M, Mejillano M, Yin HL | title = Gelsolin, a multifunctional actin regulatory protein | journal = The Journal of Biological Chemistry | volume = 274 | issue = 47 | pages = 33179–82 | date = November 1999 | pmid = 10559185 | doi = 10.1074/jbc.274.47.33179 | doi-access = free }}</ref>

Cellular gelsolin, found within the [cytosol](/source/cytosol) and [mitochondria](/source/mitochondria),<ref name="Koya">{{cite journal | vauthors = Koya RC, 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 = The Journal of Biological Chemistry | volume = 275 | issue = 20 | pages = 15343–9 | date = May 2000 | pmid = 10809769 | doi = 10.1074/jbc.275.20.15343 | doi-access = free | hdl = 2115/718 | hdl-access = free }}</ref> has a closely related secreted form, [plasma gelsolin](/source/plasma_gelsolin), that contains an additional 24 AA N-terminal extension.<ref name=Kwiatkowski1986>{{cite journal | vauthors = Kwiatkowski DJ, Stossel TP, Orkin SH, Mole JE, Colten HR, Yin HL | title = Plasma and cytoplasmic gelsolins are encoded by a single gene and contain a duplicated actin-binding domain | journal = Nature | volume = 323 | issue = 6087 | pages = 455–8 | date = 1986-10-02 | pmid = 3020431 | doi = 10.1038/323455a0 | s2cid = 4356162 | bibcode = 1986Natur.323..455K }}</ref><ref name="Nag2013Gymnast">{{cite journal | vauthors = Nag S, Larsson M, Robinson RC, Burtnick LD | title = Gelsolin: the tail of a molecular gymnast | journal = Cytoskeleton | volume = 70 | issue = 7 | pages = 360–84 | date = July 2013 | pmid = 23749648 | doi = 10.1002/cm.21117 | s2cid = 23646422 | doi-access = free }}</ref> Plasma gelsolin's ability to sever [actin filaments](/source/Actin) helps the body recover from disease and injury that leaks cellular actin into the blood. Additionally it plays important roles in host [innate immunity](/source/Innate_immune_system), activating [macrophages](/source/macrophages) and localizing of [inflammation](/source/inflammation).

== 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](/source/%CE%B2-sheet), flanked by two [α-helices](/source/%CE%B1-helix), one positioned perpendicular with respect to the strands and one positioned parallel.  The β-sheets of the three [N-terminal](/source/N-terminal) subdomains (S1-S3) join to form an extended β-sheet, as do the β-sheets of the [C-terminal](/source/C-terminal) subdomains (S4-S6).<ref name="Kiselar">{{cite journal | vauthors = Kiselar JG, Janmey PA, Almo SC, Chance MR | title = Visualizing the Ca2+-dependent activation of gelsolin by using synchrotron footprinting | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 7 | pages = 3942–7 | date = April 2003 | pmid = 12655044 | pmc = 153027 | doi = 10.1073/pnas.0736004100 | bibcode = 2003PNAS..100.3942K | doi-access = free }}</ref>

== Regulation ==
Among the [lipid](/source/lipid)-binding actin regulatory proteins, gelsolin (like [cofilin](/source/cofilin)) preferentially binds polyphosphoinositide (PPI).<ref name="Yu">{{cite journal | vauthors = Yu FX, Sun HQ, Janmey PA, Yin HL | title = Identification of a polyphosphoinositide-binding sequence in an actin monomer-binding domain of gelsolin | journal = The Journal of Biological Chemistry | volume = 267 | issue = 21 | pages = 14616–21 | date = July 1992 | doi = 10.1016/S0021-9258(18)42086-8 | pmid = 1321812 | doi-access = free }}</ref> The binding sequences in gelsolin closely resemble the motifs in the other PPI-binding proteins.<ref name="Yu" />

Gelsolin's activity is stimulated by calcium ions (Ca<sup>2+</sup>).<ref name="Sun" /> 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.<ref name="Burtnik">{{cite journal | vauthors = Burtnick LD, Urosev D, Irobi E, Narayan K, Robinson RC | title = Structure of the N-terminal half of gelsolin bound to actin: roles in severing, apoptosis and FAF | journal = The EMBO Journal | volume = 23 | issue = 14 | pages = 2713–22 | date = July 2004 | pmid = 15215896 | pmc = 514944 | doi = 10.1038/sj.emboj.7600280 }}</ref> The C-terminal end detects the calcium concentration within the cell. When there is no Ca<sup>2+</sup> present, the tail of S6 shields the actin-binding sites on one of S2's helices.<ref name="Kiselar" /> When a calcium ion attaches to the S6 tail, however, it straightens, exposing the S2 actin-binding sites.<ref name="Burtnik" /> 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.<ref name="Yu" />

Gelsolin can be inhibited by a local rise in the concentration of [phosphatidylinositol (4,5)-bisphosphate](/source/phosphatidylinositol_(4%2C5)-bisphosphate) (PIP<sub>2</sub>), a PPI. This is a two step process.  Firstly, (PIP<sub>2</sub>) binds to S2 and S3, inhibiting gelsolin from actin side binding. Then, (PIP<sub>2</sub>) binds to gelsolin's S1, preventing gelsolin from severing actin, although (PIP<sub>2</sub>) does not bind directly to gelsolin's actin-binding site.<ref name="Yu" />

Gelsolin's severing of actin, in contrast to the severing of [microtubules](/source/microtubules) by [katanin](/source/katanin), does not require any extra energy input.

==Cellular function==

As an important actin regulator, gelsolin plays a role in [podosome](/source/podosome) formation (along with Arp3, [cortactin](/source/cortactin), and Rho GTPases).<ref name="Varon">{{cite journal | vauthors = Varon C, Tatin F, Moreau V, Van Obberghen-Schilling E, Fernandez-Sauze S, Reuzeau E, Kramer I, Génot E | display-authors = 6 | title = Transforming growth factor beta induces rosettes of podosomes in primary aortic endothelial cells | journal = Molecular and Cellular Biology | volume = 26 | issue = 9 | pages = 3582–94 | date = May 2006 | pmid = 16611998 | pmc = 1447430 | doi = 10.1128/MCB.26.9.3582-3594.2006 }}</ref>

Gelsolin also inhibits [apoptosis](/source/apoptosis) by stabilizing the [mitochondria](/source/mitochondria).<ref name="Koya" /> Prior to cell death, mitochondria normally lose [membrane potential](/source/membrane_potential) and become more permeable. Gelsolin can impede the release of [cytochrome C](/source/cytochrome_C), obstructing the signal amplification that would have led to apoptosis.<ref name=pmid11039896>{{cite journal | vauthors = Kusano H, Shimizu S, Koya RC, Fujita H, Kamada S, Kuzumaki N, Tsujimoto Y | title = Human gelsolin prevents apoptosis by inhibiting apoptotic mitochondrial changes via closing VDAC | journal = Oncogene | volume = 19 | issue = 42 | pages = 4807–14 | date = October 2000 | pmid = 11039896 | doi = 10.1038/sj.onc.1203868 | doi-access =  }}</ref>

Actin can be cross-linked into a [gel](/source/gel) by actin cross-linking proteins. Gelsolin can turn this gel into a [sol](/source/Sol_(colloid)), hence the name gelsolin.

== Animal studies ==

Research in mice suggests that gelsolin, like other actin-severing proteins, is not expressed to a significant degree until after the early [embryo](/source/embryo)nic stage—approximately 2 weeks in [murine](/source/murine) embryos.<ref name="Witke">{{cite journal | vauthors = Witke W, Sharpe AH, Hartwig JH, Azuma T, Stossel TP, Kwiatkowski DJ | title = Hemostatic, inflammatory, and fibroblast responses are blunted in mice lacking gelsolin | journal = Cell | volume = 81 | issue = 1 | pages = 41–51 | date = April 1995 | pmid = 7720072 | doi = 10.1016/0092-8674(95)90369-0 | doi-access = free }}</ref> In adult specimens, however, gelsolin is particularly important in motile cells, such as blood [platelet](/source/platelet)s. Mice with null gelsolin-coding [genes](/source/genes) undergo normal [embryonic development](/source/Embryogenesis), but the deformation of their blood platelets reduced their motility, resulting in a slower response to wound healing.<ref name="Witke" />

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.<ref name="Becker">{{cite journal | vauthors = Becker PM, Kazi AA, Wadgaonkar R, Pearse DB, Kwiatkowski D, Garcia JG | title = Pulmonary vascular permeability and ischemic injury in gelsolin-deficient mice | journal = American Journal of Respiratory Cell and Molecular Biology | volume = 28 | issue = 4 | pages = 478–84 | date = April 2003 | pmid = 12654637 | doi = 10.1165/rcmb.2002-0024OC }}</ref>

== Related proteins ==
{{Infobox protein family
| align = left
| Name = Gelsolin-like domain
| image = Villin domain 6.png
| width = 
| caption = {{PDB2|3FG7}}; Villin-1 domain 6: a gelsolin-like domain. The long helix is straight, consistent with the Ca<sup>2+</sup>-activated form of gelsolin.<ref>{{cite journal | vauthors = Wang H, Chumnarnsilpa S, Loonchanta A, Li Q, Kuan YM, Robine S, Larsson M, Mihalek I, Burtnick LD, Robinson RC | display-authors = 6 | title = Helix straightening as an activation mechanism in the gelsolin superfamily of actin regulatory proteins | journal = The Journal of Biological Chemistry | volume = 284 | issue = 32 | pages = 21265–9 | date = August 2009 | pmid = 19491107 | pmc = 2755850 | doi = 10.1074/jbc.M109.019760 | doi-access = free }}</ref>}}
[Sequence](/source/sequence_(biology)) comparisons indicate an [evolution](/source/evolution)ary relationship between gelsolin, [villin](/source/villin), [fragmin](/source/Fragmin_(protein)), and [severin](/source/Severin_(protein)).<ref name="pmid2850369">{{cite journal | vauthors = Way M, Weeds A | title = Nucleotide sequence of pig plasma gelsolin. Comparison of protein sequence with human gelsolin and other actin-severing proteins shows strong homologies and evidence for large internal repeats | journal = Journal of Molecular Biology | volume = 203 | issue = 4 | pages = 1127–33 | date = October 1988 | pmid = 2850369 | doi = 10.1016/0022-2836(88)90132-5 }}</ref> Six large repeating segments occur in gelsolin and villin, and 3 similar segments in severin and fragmin. The multiple [repeat](/source/tandem_repeat)s are related in structure (but barely in sequence) to the [ADF-H domain](/source/ADF-H_domain), forming a superfamily ({{InterPro|IPR029006}}). The [family](/source/Protein_family) appears to have [evolved](/source/evolution) from an ancestral [sequence](/source/sequence) of 120 to 130 [amino acid](/source/amino_acid) [residues](/source/residue_(chemistry)).<ref name="pmid2850369"/><ref name="pmid24155256" />

[Asgard archaea](/source/Asgard_archaea) encode many functional gelsolins.<ref>{{cite journal | vauthors = Akıl C, Tran LT, Orhant-Prioux M, Baskaran Y, Manser E, Blanchoin L, Robinson RC | title = Insights into the evolution of regulated actin dynamics via characterization of primitive gelsolin/cofilin proteins from Asgard archaea | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 117 | issue = 33 | pages = 19904–19913 | date = August 2020 | pmid = 32747565 | doi = 10.1073/pnas.2009167117 | pmc = 7444086 | bibcode = 2020PNAS..11719904A | doi-access = free }}</ref>

== Interactions ==

Gelsolin is a [cytoplasm](/source/cytoplasm)ic, calcium-regulated, actin-modulating [protein](/source/protein) that binds to the barbed ends of [actin](/source/actin) filaments, preventing [monomer](/source/monomer) exchange (end-blocking or capping).<ref name="pmid3023087">{{cite journal | vauthors = Weeds AG, Gooch J, Pope B, Harris HE | title = Preparation and characterization of pig plasma and platelet gelsolins | journal = European Journal of Biochemistry | volume = 161 | issue = 1 | pages = 69–76 | date = November 1986 | pmid = 3023087 | doi = 10.1111/j.1432-1033.1986.tb10125.x | doi-access = free }}</ref> It can promote nucleation (the assembly of monomers into filaments), as well as sever existing [filaments](/source/Protein_filament). In addition, this protein binds with high affinity to [fibronectin](/source/fibronectin). [Plasma gelsolin](/source/Plasma_gelsolin) and cytoplasmic gelsolin are derived from a single [gene](/source/gene) by alternate initiation sites and differential [splicing](/source/splicing_(genetics)).<ref name=Kwiatkowski1986 />

Gelsolin has been shown to [interact](/source/Protein-protein_interaction) with:
* [Amyloid precursor protein](/source/Amyloid_precursor_protein),<ref name="pmid10329371">{{cite journal | vauthors = Chauhan VP, Ray I, Chauhan A, Wisniewski HM | title = Binding of gelsolin, a secretory protein, to amyloid beta-protein | journal = Biochemical and Biophysical Research Communications | volume = 258 | issue = 2 | pages = 241–6 | date = May 1999 | pmid = 10329371 | doi = 10.1006/bbrc.1999.0623 }}</ref>
* [Androgen receptor](/source/Androgen_receptor),<ref name="pmid12941811">{{cite journal | vauthors = Nishimura K, Ting HJ, Harada Y, Tokizane T, Nonomura N, Kang HY, Chang HC, Yeh S, Miyamoto H, Shin M, Aozasa K, Okuyama A, Chang C | display-authors = 6 | title = Modulation of androgen receptor transactivation by gelsolin: a newly identified androgen receptor coregulator | journal = Cancer Research | volume = 63 | issue = 16 | pages = 4888–94 | date = August 2003 | pmid = 12941811 }}</ref>
* [PTK2B](/source/PTK2B),<ref name="pmid12578912">{{cite journal | vauthors = Wang Q, Xie Y, Du QS, Wu XJ, Feng X, Mei L, McDonald JM, Xiong WC | display-authors = 6 | title = Regulation of the formation of osteoclastic actin rings by proline-rich tyrosine kinase 2 interacting with gelsolin | journal = The Journal of Cell Biology | volume = 160 | issue = 4 | pages = 565–75 | date = February 2003 | pmid = 12578912 | pmc = 2173747 | doi = 10.1083/jcb.200207036 }}</ref> and
* [VDAC1](/source/VDAC1).<ref name="pmid11039896"/>

== See also ==
* [Plasma gelsolin](/source/Plasma_gelsolin)
* [Cortactin](/source/Cortactin)
* [Villin](/source/Villin)
* [Supervillin](/source/Supervillin)
* [Finnish type amyloidosis](/source/Finnish_type_amyloidosis)
{{clear}}

== References ==
{{reflist|30em}}

== External links ==
* {{MeshName|Gelsolin}}
{{Calcium-binding proteins}}
{{Cytoskeletal Proteins}}

{{PDB_Gallery|geneid=2934}}
* http://www.bioaegistherapeutics.com

Category:Proteins

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Adapted from the Wikipedia article [Gelsolin](https://en.wikipedia.org/wiki/Gelsolin) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Gelsolin?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.