Gelsolin

GSN
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1C0F, 1C0G, 1D4X, 1DEJ, 1EQY, 1ESV, 1H1V, 1KCQ, 1MDU, 1NLV, 1NM1, 1NMD, 1P8X, 1P8Z, 1SOL, 1T44, 1YAG, 1YVN, 2FF3, 2FF6, 2FH1, 2FH2, 2FH3, 2FH4, 3A5L, 3A5M, 3A5N, 3A5O, 3CI5, 3CIP, 3CJB, 3CJC, 3FFK, 3FFN, 3TU5, 4PKG, 4PKH, 4PKI, 4S10, 4Z94
Identifiers
Aliases	GSN, Gsn, ADF, AGEL, gelsolin
External IDs	OMIM: 137350 MGI: 95851 HomoloGene: 147 GeneCards: GSN
Gene location (Mouse) Chr. Chromosome 2 (mouse)[1] Band 2 B|2 23.5 cM Start 35,146,392 bp[1] End 35,197,904 bp[1]
RNA expression pattern Bgee Human Mouse (ortholog) n/a Top expressed in subcutaneous adipose tissue right lung white adipose tissue right lung lobe left lung superior surface of tongue conjunctival fornix intercostal muscle ankle aortic valve BioGPS More reference expression data
Gene ontology Molecular function metal ion binding protein binding actin binding myosin II binding calcium ion binding actin filament binding Cellular component cytoplasm cytosol blood microparticle plasma membrane extracellular region sarcoplasm cortical actin cytoskeleton actin cap podosome extracellular exosome cytoskeleton nucleus secretory granule lumen ficolin-1-rich granule lumen ruffle extracellular space focal adhesion actin cytoskeleton lamellipodium myelin sheath perinuclear region of cytoplasm protein-containing complex phagocytic vesicle Biological process regulation of plasma membrane raft polarization cilium assembly sequestering of actin monomers actin filament reorganization amyloid fibril formation positive regulation of keratinocyte apoptotic process striated muscle atrophy regulation of establishment of T cell polarity extracellular matrix disassembly positive regulation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway positive regulation of actin nucleation regulation of receptor clustering positive regulation of gene expression cell projection organization protein destabilization actin filament capping regulation of podosome assembly renal protein absorption hepatocyte apoptotic process neutrophil degranulation actin nucleation actin filament severing barbed-end actin filament capping phagocytosis, engulfment apoptotic process human ageing actin polymerization or depolymerization oligodendrocyte development vesicle-mediated transport actin filament polymerization regulation of cell adhesion wound healing tissue regeneration response to ethanol phosphatidylinositol-mediated signaling response to folic acid cellular response to cadmium ion positive regulation of protein processing in phagocytic vesicle cellular response to interferon-gamma Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2934 227753 Ensembl ENSG00000148180 ENSMUSG00000026879 UniProt P06396 P13020 RefSeq (mRNA) NM_000177 NM_001127662 NM_001127663 NM_001127664 NM_001127665 NM_001127666 NM_001127667 NM_001258029 NM_001258030 NM_198252 NM_001206367 NM_001206368 NM_001206369 NM_146120 NM_001362945 NM_001362947 NM_001362948 RefSeq (protein) NP_000168 NP_001121134 NP_001121135 NP_001121136 NP_001121137 NP_001121138 NP_001121139 NP_001244958 NP_001244959 NP_937895 NP_001339982 NP_001339983 NP_001339984 NP_001339985 NP_001339986 NP_001339987 NP_001339988 NP_001339989 NP_001339990 NP_001339991 NP_001339992 NP_001339993 NP_001339994 NP_001339995 NP_001339996 NP_001339997 NP_001339998 NP_001339999 NP_001340000 NP_001340001 NP_001340002 NP_001340003 NP_001340004 NP_001340005 NP_001340006 NP_001340007 NP_001193296 NP_001193297 NP_001193298 NP_666232 NP_001349874 NP_001349876 NP_001349877 Location (UCSC) n/a Chr 2: 35.15 – 35.2 Mb PubMed search [2] [3]
Wikidata
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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]

Related proteins

Gelsolin-like domain
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:

• Amyloid precursor protein,^[20]
• Androgen receptor,^[21]
• PTK2B,^[22] and
• VDAC1.^[13]

See also

• Plasma gelsolin
• Cortactin
• Villin
• Supervillin
• Finnish type amyloidosis

References

External links

• Gelsolin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

• http://www.bioaegistherapeutics.com