Biology:Gelsolin

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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][2]

Cellular gelsolin, found within the cytosol and mitochondria,[3] has a closely related secreted form, Plasma gelsolin, that contains an additional 24 AA N-terminal extension.[4][5] 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).[6]

Regulation

Among the lipid-binding actin regulatory proteins, gelsolin (like cofilin) preferentially binds polyphosphoinositide (PPI).[7] The binding sequences in gelsolin closely resemble the motifs in the other PPI-binding proteins.[7]

Gelsolin's activity is stimulated by calcium ions (Ca2+).[2] 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.[8] 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.[6] When a calcium ion attaches to the S6 tail, however, it straightens, exposing the S2 actin-binding sites.[8] 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.[7]

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.[7]

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).[9]

Gelsolin also inhibits apoptosis by stabilizing the mitochondria.[3] 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.[10]

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.[11] 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.[11]

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.[12]

Related proteins

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.[13]
Identifiers
Symbol?

Sequence comparisons indicate an evolutionary relationship between gelsolin, villin, fragmin, and severin.[14] 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.[14][1]

Asgard archaea encode many functional gelsolins.[15]

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).[16] 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.[4]

Gelsolin has been shown to interact with:

See also

References

  1. ↑ 1.0 1.1 "The expanding superfamily of gelsolin homology domain proteins". Cytoskeleton 70 (11): 775–95. November 2013. doi:10.1002/cm.21149. PMID 24155256. 
  2. ↑ 2.0 2.1 "Gelsolin, a multifunctional actin regulatory protein". The Journal of Biological Chemistry 274 (47): 33179–82. November 1999. doi:10.1074/jbc.274.47.33179. PMID 10559185. 
  3. ↑ 3.0 3.1 "Gelsolin inhibits apoptosis by blocking mitochondrial membrane potential loss and cytochrome c release". The Journal of Biological Chemistry 275 (20): 15343–9. May 2000. doi:10.1074/jbc.275.20.15343. PMID 10809769. 
  4. ↑ 4.0 4.1 "Plasma and cytoplasmic gelsolins are encoded by a single gene and contain a duplicated actin-binding domain". Nature 323 (6087): 455–8. 1986-10-02. doi:10.1038/323455a0. PMID 3020431. Bibcode: 1986Natur.323..455K. 
  5. ↑ "Gelsolin: the tail of a molecular gymnast". Cytoskeleton 70 (7): 360–84. July 2013. doi:10.1002/cm.21117. PMID 23749648. 
  6. ↑ 6.0 6.1 "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. April 2003. doi:10.1073/pnas.0736004100. PMID 12655044. Bibcode: 2003PNAS..100.3942K. 
  7. ↑ 7.0 7.1 7.2 7.3 "Identification of a polyphosphoinositide-binding sequence in an actin monomer-binding domain of gelsolin". The Journal of Biological Chemistry 267 (21): 14616–21. July 1992. doi:10.1016/S0021-9258(18)42086-8. PMID 1321812. 
  8. ↑ 8.0 8.1 "Structure of the N-terminal half of gelsolin bound to actin: roles in severing, apoptosis and FAF". The EMBO Journal 23 (14): 2713–22. July 2004. doi:10.1038/sj.emboj.7600280. PMID 15215896. 
  9. ↑ "Transforming growth factor beta induces rosettes of podosomes in primary aortic endothelial cells". Molecular and Cellular Biology 26 (9): 3582–94. May 2006. doi:10.1128/MCB.26.9.3582-3594.2006. PMID 16611998. 
  10. ↑ 10.0 10.1 "Human gelsolin prevents apoptosis by inhibiting apoptotic mitochondrial changes via closing VDAC". Oncogene 19 (42): 4807–14. October 2000. doi:10.1038/sj.onc.1203868. PMID 11039896. 
  11. ↑ 11.0 11.1 "Hemostatic, inflammatory, and fibroblast responses are blunted in mice lacking gelsolin". Cell 81 (1): 41–51. April 1995. doi:10.1016/0092-8674(95)90369-0. PMID 7720072. 
  12. ↑ "Pulmonary vascular permeability and ischemic injury in gelsolin-deficient mice". American Journal of Respiratory Cell and Molecular Biology 28 (4): 478–84. April 2003. doi:10.1165/rcmb.2002-0024OC. PMID 12654637. 
  13. ↑ "Helix straightening as an activation mechanism in the gelsolin superfamily of actin regulatory proteins". The Journal of Biological Chemistry 284 (32): 21265–9. August 2009. doi:10.1074/jbc.M109.019760. PMID 19491107. 
  14. ↑ 14.0 14.1 "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. October 1988. doi:10.1016/0022-2836(88)90132-5. PMID 2850369. 
  15. ↑ "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. August 2020. doi:10.1073/pnas.2009167117. PMID 32747565. Bibcode: 2020PNAS..11719904A. 
  16. ↑ "Preparation and characterization of pig plasma and platelet gelsolins". European Journal of Biochemistry 161 (1): 69–76. November 1986. doi:10.1111/j.1432-1033.1986.tb10125.x. PMID 3023087. 
  17. ↑ "Binding of gelsolin, a secretory protein, to amyloid beta-protein". Biochemical and Biophysical Research Communications 258 (2): 241–6. May 1999. doi:10.1006/bbrc.1999.0623. PMID 10329371. 
  18. ↑ "Modulation of androgen receptor transactivation by gelsolin: a newly identified androgen receptor coregulator". Cancer Research 63 (16): 4888–94. August 2003. PMID 12941811. 
  19. ↑ "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. February 2003. doi:10.1083/jcb.200207036. PMID 12578912. 

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