Gelsolin

Gelsolin
crystal structure of the copii coat subunit, sec24, complexed with a peptide from the snare protein sed5 (yeast syntaxin-5)
Identifiers
Symbol	Gelsolin
Pfam	PF00626
Pfam clan	CL0092
InterPro	IPR007123
SCOP	1vil
SUPERFAMILY	1vil
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Gelsolin
PDB rendering based on 1c0f.
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
Identifiers
Symbols	GSN ; ADF; AGEL
External IDs	OMIM: 137350 MGI: 95851 HomoloGene: 147 GeneCards: GSN Gene
Gene ontology Molecular function • actin binding • calcium ion binding • protein binding • protein domain specific binding • myosin II binding Cellular component • ruffle • podosome • extracellular region • extracellular space • nucleus • cytoplasm • cytosol • plasma membrane • focal adhesion • actin cytoskeleton • sarcoplasm • lamellipodium • actin cap • cortical actin cytoskeleton • myelin sheath • perinuclear region of cytoplasm • extracellular exosome • blood microparticle Biological process • phagocytosis, engulfment • apoptotic process • cellular component disassembly involved in execution phase of apoptosis • aging • positive regulation of gene expression • programmed cell death • oligodendrocyte development • striated muscle atrophy • extracellular matrix disassembly • actin filament polymerization • protein destabilization • tissue regeneration • sequestering of actin monomers • actin nucleation • response to ethanol • negative regulation of viral entry into host cell • phosphatidylinositol-mediated signaling • actin filament severing • barbed-end actin filament capping • positive regulation of actin nucleation • response to folic acid • actin filament capping • cilium morphogenesis • cellular response to cadmium ion • regulation of podosome assembly • actin filament reorganization • renal protein absorption • hepatocyte apoptotic process • positive regulation of keratinocyte apoptotic process • regulation of wound healing, spreading of epidermal cells • regulation of establishment of T cell polarity • regulation of plasma membrane raft polarization • regulation of receptor clustering • positive regulation of protein processing in phagocytic vesicle • amyloid fibril formation • positive regulation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2934	227753
Ensembl	ENSG00000148180	ENSMUSG00000026879
UniProt	P06396	P13020
RefSeq (mRNA)	NM_000177	NM_001206367
RefSeq (protein)	NP_000168	NP_001193296
Location (UCSC)	Chr 9: 121.21 – 121.33 Mb	Chr 2: 35.28 – 35.31 Mb
PubMed search	[1]	[2]

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. Gelsolin is located intracellularly (in cytosol and mitochondria) and extracellularly (in blood plasma).

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 N-terminal (S1-S3) forms an extended β-sheet, as does the C-terminal (S4-S6).

Regulation

Among the lipid-binding actin regulatory proteins, gelsolin (along with cofilin) is one of the few that exhibit preferential binding toward polyphosphoinositide (PPIs). The binding sequences in gelsolin closely resemble the motifs in the other PPI-binding proteins.

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

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.

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).

Gelsolin also inhibits apoptosis by stabilizing the mitochondria. 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.

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. 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.

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.

Related proteins

Sequence comparisons indicate an evolutionary relationship between gelsolin, villin, fragmin and severin. Six large repeating segments occur in gelsolin and villin, and 3 similar segments in severin and fragmin. While the multiple repeats have yet to be related to any known function of the actin-severing proteins, the superfamily appears to have evolved from an ancestral sequence of 120 to 130 amino acid residues.

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). 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.

Gelsolin has been shown to interact with:

• Amyloid precursor protein,
• Androgen receptor,
• PTK2B, and
• VDAC1.

See also

• Cortactin
• Villin
• Supervillin
• Finnish type amyloidosis

External links

• Gelsolin at the US National Library of Medicine Medical Subject Headings (MeSH)

• http://www.bioaegistherapeutics.com