Gelsolin is anactin-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 thecytosol andmitochondria,[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 severactin filaments helps the body recover from disease and injury that leaks cellular actin into the blood. Additionally it plays important roles in hostinnate immunity, activatingmacrophages and localizing ofinflammation.
Gelsolin is an 82-kD protein with six homologous subdomains, referred to as S1-S6. Each subdomain is composed of a five-strandedβ-sheet, flanked by twoα-helices, one positioned perpendicular with respect to the strands and one positioned parallel. The β-sheets of the threeN-terminal subdomains (S1-S3) join to form an extended β-sheet, as do the β-sheets of theC-terminal subdomains (S4-S6).[9]
Among thelipid-binding actin regulatory proteins, gelsolin (likecofilin) 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 ofphosphatidylinositol (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 ofmicrotubules bykatanin, does not require any extra energy input.
As an important actin regulator, gelsolin plays a role inpodosome formation (along with Arp3,cortactin, and Rho GTPases).[12]
Gelsolin also inhibitsapoptosis by stabilizing themitochondria.[6] Prior to cell death, mitochondria normally losemembrane potential and become more permeable. Gelsolin can impede the release ofcytochrome C, obstructing the signal amplification that would have led to apoptosis.[13]
Actin can be cross-linked into agel by actin cross-linking proteins. Gelsolin can turn this gel into asol, 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 earlyembryonic stage—approximately 2 weeks inmurine embryos.[14] In adult specimens, however, gelsolin is particularly important in motile cells, such as bloodplatelets. Mice with null gelsolin-codinggenes undergo normalembryonic 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 is acytoplasmic, calcium-regulated, actin-modulatingprotein that binds to the barbed ends ofactin filaments, preventingmonomer exchange (end-blocking or capping).[19] It can promote nucleation (the assembly of monomers into filaments), as well as sever existingfilaments. In addition, this protein binds with high affinity tofibronectin.Plasma gelsolin and cytoplasmic gelsolin are derived from a singlegene by alternate initiation sites and differentialsplicing.[7]
^abKwiatkowski 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.PMID3020431.S2CID4356162.
^abWay 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.PMID2850369.
^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.PMID10329371.
^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.PMID12941811.
1c0f: CRYSTAL STRUCTURE OF DICTYOSTELIUM CAATP-ACTIN IN COMPLEX WITH GELSOLIN SEGMENT 1
1c0g: CRYSTAL STRUCTURE OF 1:1 COMPLEX BETWEEN GELSOLIN SEGMENT 1 AND A DICTYOSTELIUM/TETRAHYMENA CHIMERA ACTIN (MUTANT 228: Q228K/T229A/A230Y/E360H)
1d0n: THE CRYSTAL STRUCTURE OF CALCIUM-FREE EQUINE PLASMA GELSOLIN.
1d4x: Crystal Structure of Caenorhabditis Elegans Mg-ATP Actin Complexed with Human Gelsolin Segment 1 at 1.75 A resolution.
1dej: CRYSTAL STRUCTURE OF A DICTYOSTELIUM/TETRAHYMENA CHIMERA ACTIN (MUTANT 646: Q228K/T229A/A230Y/A231K/S232E/E360H) IN COMPLEX WITH HUMAN GELSOLIN SEGMENT 1
1eqy: COMPLEX BETWEEN RABBIT MUSCLE ALPHA-ACTIN: HUMAN GELSOLIN DOMAIN 1
