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. pGSN has a cytoplasmic isoform (cGSN) known to be an actin-binding protein controlling cytoskeletal dynamics. cGSN is expressed from the same gene, and is identical to pGSN except for its lack of a 24 amino acid N-terminal extension.
History The cellular isoform of Gelsolin was discovered in 1979 in the lab of Thomas P. Stossel. Its name comes from observed calcium-dependent reversible gel-sol transitions of macrophage cytoplasmic extract. Around the same time a similarly sized plasma protein was discovered and shown to depolymerize actin; it was named Brevin, due to its ability to shorten actin filaments. In 1986 it was demonstrated that Brevin was identical to cellular Gelsolin except for a 24 AA N-terminal extension, and was renamed Plasma Gelsolin.
Structure
Plasma Gelsolin is a 755 AA, 83 kDa plasma protein made up of six "gelsolin domains," each composed of a 5-6 strand β-sheet between one long and one short α-helix. It exhibits a weak homology between domains S1 and S4, S2 and S5, and S3 and S6, and is identical to the cytoplasmic form of the protein except for the addition of a 24 AA N-terminal extension. Additionally a 27 AA N-terminal signal peptide is cleaved prior to pGSN's secretion from the cell. Both forms of the protein are encoded by highly conserved genes on chromosome 9 in humans, but are under the control of different promoters. There is a single disulfide bond formed on the second domain of the plasma protein, there are no documented natural post-translational modifications, and the pI ≈ 6.
Isoforms and mutations Aside from the cellular form, the only other known isoform is Gelsolin-3, an identical non-secreted protein containing an 11 AA, rather than 24 AA, N-terminal extension. It has been found in brain, testes, and lung oligodendrocytes, and is reportedly involved in myelin remodeling during spiralization around the axon. Plasma Gelsolin is highly conserved, and its only known mutations are single point mutations. One of several such mutations leads to Finnish Familial Amyloidosis, a disorder in which pGSN becomes more conformationally flexible and susceptible to enzymatic cleavage resulting in accumulation of peptide fragments into amyloid fibrils. D187N/Y is the most common mutation with additional reports of G167R, N184K, P432R, A551P, and Ala7fs in the medical literature. In addition to this several mutations as well as down-regulation of the protein are associated with breast cancer.
Ca2+ At moderate pH in the absence of Ca2+ pGSN is compact and globular. Low pH or the presence of >nM Ca2+ is associated with an elongated structure with greater backbone flexibility. This flexibility exposes the actin binding sites. Since physiological levels of Ca2+ are ~2 mM, pGSN is natively elongated and able to bind to leaked actin from cellular damage.
Functions
Binding Plasma Gelsolin is a sticky protein known to bind to a number of peptides and proteins: Actin (see: Relationships with actin), Apo-H, Aβ, α-Synuclein, Integrin, Tcp-1, Fibronectin, Syntaxin-4, Tropomyosin, fatty acids and phospholipids (see: Binding and inactivation of diverse inflammatory mediators): LPA, LPS (endotoxin), LTA, PAF, S1P, polyphosphoinositides including PIP2; and nucleic acids: Ap3A, ATP, ADP. PIP2, a phospholipid component of cell membranes, competes with ATP and actin for pGSN binding, and will dissociate F-Actin-capped pGSN.
Relationships with actin
Actin toxicity and removal
Actin is the most abundant cellular protein, and its release into extracellular fluid and circulation following cellular injury from disease or injury leads to increased blood viscosity, hindered microcirculation, and activation of platelets. Hemodialysis patients with low levels of pGSN and high levels of actin in blood had markedly higher mortality. Actin is a major component of biofilms that accumulate at local sites of injury and infection, impeding access of host immune components and therapeutics such as antibiotics. Biofilms are particularly pathogenic in the setting of foreign bodies like indwelling catheters and tissue implants. Actin exchanges between monomeric (G) and filamentous (F) forms according to the concentrations of it, ATP, and cations. pGSN along with Vitamin D-binding protein (DBP) bind and clear monomeric actin. DBP binds with greater affinity to G-actin, leaving pGSN available to sever F-actin. Furthermore, DBP is capable of removing one actin from a 2:1 actin-pGSN complex, restoring its ability to sever F-actin. F-actin, severed and capped by pGSN, is removed by sinusoidal endothelial cells of the liver. pGSN removes 60% of actin trapped in fibrin clots in vitro leading to an increased rate of clot lysis.
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![Plasma gelsolin: A solution phase representation of pGSN in the presence of Ca2+ adapted from 3FFN and low-resolution SAXS information.[12] The 24 AA N-terminal extension unique to the plasma isoform was manually added (left, light blue); no structural information for it is known nor represented. Colors represent the six domains of Gelsolin.[13][14]](https://upload.wikimedia.org/wikipedia/commons/thumb/b/b6/3FFN_solution_structure_no_binding.png/1280px-3FFN_solution_structure_no_binding.png?utm_source=en.wikipedia.org&utm_campaign=parser&utm_content=thumbnail)
