Gelsolin

Last updated
GSN
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Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases GSN , Gsn, ADF, AGEL, gelsolin
External IDs OMIM: 137350 MGI: 95851 HomoloGene: 147 GeneCards: GSN
Orthologs
SpeciesHumanMouse
Entrez

2934

227753

Ensembl

ENSG00000148180

ENSMUSG00000026879

UniProt

P06396

P13020

RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)n/a Chr 2: 35.15 – 35.2 Mb
PubMed search [2] [3]
Wikidata
View/Edit Human View/Edit Mouse

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. [4] [5]

Cellular gelsolin, found within the cytosol and mitochondria, [6] has a closely related secreted form, Plasma gelsolin, that contains an additional 24 AA N-terminal extension. [7] [8] Plasma gelsolin's ability to sever actin filaments helps the body recover from disease and injury that leaks cellular actin into the blood. Additionally it plays important roles in host innate immunity, activating macrophages and localizing of 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, flanked by two α-helices, one positioned perpendicular with respect to the strands and one positioned parallel. The β-sheets of the three N-terminal subdomains (S1-S3) join to form an extended β-sheet, as do the β-sheets of the C-terminal subdomains (S4-S6). [9]

Regulation

Among the lipid-binding actin regulatory proteins, gelsolin (like cofilin) preferentially binds polyphosphoinositide (PPI). [10] The binding sequences in gelsolin closely resemble the motifs in the other PPI-binding proteins. [10]

Gelsolin's activity is stimulated by calcium ions (Ca2+). [5] 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. [11] 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. [9] When a calcium ion attaches to the S6 tail, however, it straightens, exposing the S2 actin-binding sites. [11] 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. [10]

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. [10]

Gelsolin's severing of actin, in contrast to the severing of microtubules by katanin, does not require any extra energy input.

Cellular function

As an important actin regulator, gelsolin plays a role in podosome formation (along with Arp3, cortactin, and Rho GTPases). [12]

Gelsolin also inhibits apoptosis by stabilizing the mitochondria. [6] 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. [13]

Actin can be cross-linked into a gel by actin cross-linking proteins. Gelsolin can turn this gel into a sol, 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 embryonic stage—approximately 2 weeks in murine embryos. [14] 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. [14]

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. [15]

Gelsolin-like domain
Villin domain 6.png
3FG7 ​; Villin-1 domain 6: a gelsolin-like domain. The long helix is straight, consistent with the Ca2+-activated form of gelsolin. [16]
Identifiers
Symbol?

Sequence comparisons indicate an evolutionary relationship between gelsolin, villin, fragmin, and severin. [17] Six large repeating segments occur in gelsolin and villin, and 3 similar segments in severin and fragmin. The multiple repeats are related in structure (but barely in sequence) to the ADF-H domain, forming a superfamily (InterPro :  IPR029006 ). The family appears to have evolved from an ancestral sequence of 120 to 130 amino acid residues. [17] [4]

Asgard archaea encode many functional gelsolins. [18]

Interactions

Gelsolin is a cytoplasmic, calcium-regulated, actin-modulating protein that binds to the barbed ends of actin filaments, preventing monomer exchange (end-blocking or capping). [19] It can promote nucleation (the assembly of monomers into filaments), as well as sever existing filaments. In addition, this protein binds with high affinity to fibronectin. Plasma gelsolin and cytoplasmic gelsolin are derived from a single gene by alternate initiation sites and differential splicing. [7]

Gelsolin has been shown to interact with:

See also

Related Research Articles

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<span class="mw-page-title-main">Microfilament</span> Filament in the cytoplasm of eukaryotic cells

Microfilaments, also called actin filaments, are protein filaments in the cytoplasm of eukaryotic cells that form part of the cytoskeleton. They are primarily composed of polymers of actin, but are modified by and interact with numerous other proteins in the cell. Microfilaments are usually about 7 nm in diameter and made up of two strands of actin. Microfilament functions include cytokinesis, amoeboid movement, cell motility, changes in cell shape, endocytosis and exocytosis, cell contractility, and mechanical stability. Microfilaments are flexible and relatively strong, resisting buckling by multi-piconewton compressive forces and filament fracture by nanonewton tensile forces. In inducing cell motility, one end of the actin filament elongates while the other end contracts, presumably by myosin II molecular motors. Additionally, they function as part of actomyosin-driven contractile molecular motors, wherein the thin filaments serve as tensile platforms for myosin's ATP-dependent pulling action in muscle contraction and pseudopod advancement. Microfilaments have a tough, flexible framework which helps the cell in movement.

<span class="mw-page-title-main">Actin</span> Family of proteins

Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over 100 μM; its mass is roughly 42 kDa, with a diameter of 4 to 7 nm.

<span class="mw-page-title-main">Wiskott–Aldrich syndrome protein</span> Mammalian protein found in humans

The Wiskott–Aldrich Syndrome protein (WASp) is a 502-amino acid protein expressed in cells of the hematopoietic system that in humans is encoded by the WAS gene. In the inactive state, WASp exists in an autoinhibited conformation with sequences near its C-terminus binding to a region near its N-terminus. Its activation is dependent upon CDC42 and PIP2 acting to disrupt this interaction, causing the WASp protein to 'open'. This exposes a domain near the WASp C-terminus that binds to and activates the Arp2/3 complex. Activated Arp2/3 nucleates new F-actin.

<span class="mw-page-title-main">Annexin</span> Protein family

Annexin is a common name for a group of cellular proteins. They are mostly found in eukaryotic organisms.

<span class="mw-page-title-main">ADF/Cofilin family</span>

ADF/cofilin is a family of actin-binding proteins associated with the rapid depolymerization of actin microfilaments that give actin its characteristic dynamic instability. This dynamic instability is central to actin's role in muscle contraction, cell motility and transcription regulation.

<span class="mw-page-title-main">Villin-1</span> Actin-binding protein

Villin-1 is a 92.5 kDa tissue-specific actin-binding protein associated with the actin core bundle of the brush border. Villin-1 is encoded by the VIL1 gene. Villin-1 contains multiple gelsolin-like domains capped by a small "headpiece" at the C-terminus consisting of a fast and independently folding three-helix bundle that is stabilized by hydrophobic interactions. The headpiece domain is a commonly studied protein in molecular dynamics due to its small size and fast folding kinetics and short primary sequence.

<span class="mw-page-title-main">Destrin</span> Protein found in humans

Destrin or DSTN is a protein which in humans is encoded by the DSTN gene. Destrin is a component protein in microfilaments.

CapZ, also known as CAPZ, CAZ1 and CAPPA1, is a capping protein that caps the barbed end of actin filaments in muscle cells.

Talin is a high-molecular-weight cytoskeletal protein concentrated at regions of cell–substratum contact and, in lymphocytes, at cell–cell contacts. Discovered in 1983 by Keith Burridge and colleagues, talin is a ubiquitous cytosolic protein that is found in high concentrations in focal adhesions. It is capable of linking integrins to the actin cytoskeleton either directly or indirectly by interacting with vinculin and α-actinin.

<span class="mw-page-title-main">Ezrin</span> Protein-coding gene in the species Homo sapiens

Ezrin also known as cytovillin or villin-2 is a protein that in humans is encoded by the EZR gene.

<span class="mw-page-title-main">Actin, cytoplasmic 2</span> Protein-coding gene in the species Homo sapiens

Actin, cytoplasmic 2, or gamma-actin is a protein that in humans is encoded by the ACTG1 gene. Gamma-actin is widely expressed in cellular cytoskeletons of many tissues; in adult striated muscle cells, gamma-actin is localized to Z-discs and costamere structures, which are responsible for force transduction and transmission in muscle cells. Mutations in ACTG1 have been associated with nonsyndromic hearing loss and Baraitser-Winter syndrome, as well as susceptibility of adolescent patients to vincristine toxicity.

<span class="mw-page-title-main">Capping protein (actin filament) muscle Z-line, alpha 1</span> Protein-coding gene in the species Homo sapiens

F-actin-capping protein subunit alpha-1 is a protein that in humans is encoded by the CAPZA1 gene.

<span class="mw-page-title-main">Macrophage-capping protein</span> Protein-coding gene in the species Homo sapiens

Macrophage-capping protein (CAPG) also known as actin regulatory protein CAP-G is a protein that in humans is encoded by the CAPG gene.

<span class="mw-page-title-main">SVIL</span> Protein-coding gene in the species Homo sapiens

Supervillin is a protein that in humans is encoded by the SVIL gene.

<span class="mw-page-title-main">SCIN</span> Protein-coding gene in the species Homo sapiens

Scinderin is a protein that in humans is encoded by the SCIN gene. Scinderin is an actin severing protein belonging to the gelsolin superfamily. It was discovered in Dr. Trifaro's laboratory at the University of Ottawa, Canada. Secretory tissues are rich in scinderin. In these tissues scinderin, a calcium dependent protein, regulates cortical actin networks. Normally secretory vesicles are excluded from release sites on the plasma membrane by the presence of a cortical actin filament network. During cell stimulation, calcium channels open allowing calcium ions to enter the secretory cell. Increase in intracellular calcium activates scinderin with the consequent actin filament severing and local dissociation of actin filament networks. This allows the movement of secretory vesicles to release sites on the plasma membrane.

<span class="mw-page-title-main">ERM protein family</span> Protein family

The ERM protein family consists of three closely related proteins, ezrin, radixin and moesin. The three paralogs, ezrin, radixin and moesin, are present in vertebrates, whereas other species have only one ERM gene. Therefore, in vertebrates these paralogs likely arose by gene duplication.

<span class="mw-page-title-main">Rho-associated protein kinase</span>

Rho-associated protein kinase (ROCK) is a kinase belonging to the AGC family of serine-threonine specific protein kinases. It is involved mainly in regulating the shape and movement of cells by acting on the cytoskeleton.

<span class="mw-page-title-main">Plasma gelsolin</span>

Plasma gelsolin (pGSN) is an 83 kDa abundant protein constituent of normal plasma and an important component of the innate immune system. The identification of pGSN in Drosophila melanogaster and C. elegans points to an ancient origin early in evolution. Its extraordinary structural conservation reflects its critical regulatory role in multiple essential functions. Its roles include the breakdown of filamentous actin released from dead cells, activation of macrophages, and localization of the inflammatory response. Substantial decreases in plasma levels are observed in acute and chronic infection and injury in both animal models and in humans. Supplementation therapies with recombinant human pGSN have been shown effective in more than 20 animal models.

<span class="mw-page-title-main">Villin 1</span> Protein-coding gene in the species Homo sapiens

Villin 1 is a protein that in humans is encoded by the VIL1 gene.

References

  1. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000026879 - Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. 1 2 Ghoshdastider U, Popp D, Burtnick LD, Robinson RC (November 2013). "The expanding superfamily of gelsolin homology domain proteins". Cytoskeleton. 70 (11): 775–95. doi:10.1002/cm.21149. PMID   24155256. S2CID   205643538.
  5. 1 2 Sun HQ, Yamamoto M, Mejillano M, Yin HL (November 1999). "Gelsolin, a multifunctional actin regulatory protein". The Journal of Biological Chemistry. 274 (47): 33179–82. doi: 10.1074/jbc.274.47.33179 . PMID   10559185.
  6. 1 2 Koya RC, Fujita H, Shimizu S, Ohtsu M, Takimoto M, Tsujimoto Y, Kuzumaki N (May 2000). "Gelsolin inhibits apoptosis by blocking mitochondrial membrane potential loss and cytochrome c release". The Journal of Biological Chemistry. 275 (20): 15343–9. doi: 10.1074/jbc.275.20.15343 . PMID   10809769.
  7. 1 2 Kwiatkowski DJ, Stossel TP, Orkin SH, Mole JE, Colten HR, Yin HL (1986-10-02). "Plasma and cytoplasmic gelsolins are encoded by a single gene and contain a duplicated actin-binding domain". Nature. 323 (6087): 455–8. Bibcode:1986Natur.323..455K. doi:10.1038/323455a0. PMID   3020431. S2CID   4356162.
  8. ↑ Nag S, Larsson M, Robinson RC, Burtnick LD (July 2013). "Gelsolin: the tail of a molecular gymnast". Cytoskeleton. 70 (7): 360–84. doi: 10.1002/cm.21117 . PMID   23749648. S2CID   23646422.
  9. 1 2 Kiselar JG, Janmey PA, Almo SC, Chance MR (April 2003). "Visualizing the Ca2+-dependent activation of gelsolin by using synchrotron footprinting". Proceedings of the National Academy of Sciences of the United States of America. 100 (7): 3942–7. Bibcode:2003PNAS..100.3942K. doi: 10.1073/pnas.0736004100 . PMC   153027 . PMID   12655044.
  10. 1 2 3 4 Yu FX, Sun HQ, Janmey PA, Yin HL (July 1992). "Identification of a polyphosphoinositide-binding sequence in an actin monomer-binding domain of gelsolin". The Journal of Biological Chemistry. 267 (21): 14616–21. doi: 10.1016/S0021-9258(18)42086-8 . PMID   1321812.
  11. 1 2 Burtnick LD, Urosev D, Irobi E, Narayan K, Robinson RC (July 2004). "Structure of the N-terminal half of gelsolin bound to actin: roles in severing, apoptosis and FAF". The EMBO Journal. 23 (14): 2713–22. doi:10.1038/sj.emboj.7600280. PMC   514944 . PMID   15215896.
  12. ↑ Varon C, Tatin F, Moreau V, Van Obberghen-Schilling E, Fernandez-Sauze S, Reuzeau E, et al. (May 2006). "Transforming growth factor beta induces rosettes of podosomes in primary aortic endothelial cells". Molecular and Cellular Biology. 26 (9): 3582–94. doi:10.1128/MCB.26.9.3582-3594.2006. PMC   1447430 . PMID   16611998.
  13. 1 2 Kusano H, Shimizu S, Koya RC, Fujita H, Kamada S, Kuzumaki N, Tsujimoto Y (October 2000). "Human gelsolin prevents apoptosis by inhibiting apoptotic mitochondrial changes via closing VDAC". Oncogene. 19 (42): 4807–14. doi:10.1038/sj.onc.1203868. PMID   11039896.
  14. 1 2 Witke W, Sharpe AH, Hartwig JH, Azuma T, Stossel TP, Kwiatkowski DJ (April 1995). "Hemostatic, inflammatory, and fibroblast responses are blunted in mice lacking gelsolin". Cell. 81 (1): 41–51. doi: 10.1016/0092-8674(95)90369-0 . PMID   7720072.
  15. ↑ Becker PM, Kazi AA, Wadgaonkar R, Pearse DB, Kwiatkowski D, Garcia JG (April 2003). "Pulmonary vascular permeability and ischemic injury in gelsolin-deficient mice". American Journal of Respiratory Cell and Molecular Biology. 28 (4): 478–84. doi:10.1165/rcmb.2002-0024OC. PMID   12654637.
  16. ↑ Wang H, Chumnarnsilpa S, Loonchanta A, Li Q, Kuan YM, Robine S, et al. (August 2009). "Helix straightening as an activation mechanism in the gelsolin superfamily of actin regulatory proteins". The Journal of Biological Chemistry. 284 (32): 21265–9. doi: 10.1074/jbc.M109.019760 . PMC   2755850 . PMID   19491107.
  17. 1 2 Way M, Weeds A (October 1988). "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 of Molecular Biology. 203 (4): 1127–33. doi:10.1016/0022-2836(88)90132-5. PMID   2850369.
  18. ↑ Akıl C, Tran LT, Orhant-Prioux M, Baskaran Y, Manser E, Blanchoin L, Robinson RC (August 2020). "Insights into the evolution of regulated actin dynamics via characterization of primitive gelsolin/cofilin proteins from Asgard archaea". Proceedings of the National Academy of Sciences of the United States of America. 117 (33): 19904–19913. Bibcode:2020PNAS..11719904A. doi: 10.1073/pnas.2009167117 . PMC   7444086 . PMID   32747565.
  19. ↑ Weeds AG, Gooch J, Pope B, Harris HE (November 1986). "Preparation and characterization of pig plasma and platelet gelsolins". European Journal of Biochemistry. 161 (1): 69–76. doi: 10.1111/j.1432-1033.1986.tb10125.x . PMID   3023087.
  20. ↑ Chauhan VP, Ray I, Chauhan A, Wisniewski HM (May 1999). "Binding of gelsolin, a secretory protein, to amyloid beta-protein". Biochemical and Biophysical Research Communications. 258 (2): 241–6. doi:10.1006/bbrc.1999.0623. PMID   10329371.
  21. ↑ Nishimura K, Ting HJ, Harada Y, Tokizane T, Nonomura N, Kang HY, et al. (August 2003). "Modulation of androgen receptor transactivation by gelsolin: a newly identified androgen receptor coregulator". Cancer Research. 63 (16): 4888–94. PMID   12941811.
  22. ↑ Wang Q, Xie Y, Du QS, Wu XJ, Feng X, Mei L, et al. (February 2003). "Regulation of the formation of osteoclastic actin rings by proline-rich tyrosine kinase 2 interacting with gelsolin". The Journal of Cell Biology. 160 (4): 565–75. doi:10.1083/jcb.200207036. PMC   2173747 . PMID   12578912.
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