Gelsolin
Encyclopedia
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
).
-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.
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.
nic stage—approximately 2 weeks in murine embryos. In adult specimens, however, gelsolin is particularly important in motile cells, such as blood platelet
s. 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.
comparisons indicate an evolution
ary 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 repeat
s 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
.
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 cytoplasm
ic gelsolin are derived from a single gene
by alternate initiation sites and differential splicing
.
Gelsolin has been shown to interact
with VDAC1
, Amyloid precursor protein
, Androgen receptor
and PTK2B
.
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
-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
Villin
Villin is a 92.5 kDa tissue-specific actin-binding protein associated with the actin core bundle of the brush border. Villin contains multiple gelsolin-like domains capped by a small "headpiece" at the C-terminus consisting of a fast and independently-folding three-helix bundle that is stabilized...
superfamily, as it severs with nearly 100% efficiency. Gelsolin is located intracellularly (in cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
and mitochondria) and extracellularly (in blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
).
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 lipidLipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
-binding actin regulatory proteins, gelsolin (along with cofilin
Cofilin
ADF/cofilin is a family of actin-binding proteins which disassembles actin filaments.Three highly conserved and highly identical genes belonging to this family have been described in human and mice:...
) 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
Phosphatidylinositol (4,5)-bisphosphate
Phosphatidylinositol 4,5-bisphosphate or PtdInsP2, also known simply as PIP2, is a minor phospholipid component of cell membranes...
(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
Katanin
Katanin is a microtubule-severing AAA protein. It is named after the Japanese sword, katana. Katanin is a heterodimeric protein first discovered in sea urchins. It contains a 60 kDa ATPase subunit, which functions to sever microtubules. This subunit requires ATP and the presence of microtubules...
, does not require any extra energy input.
Cellular Function
As an important actin regulator, gelsolin plays a role in podosomePodosome
Podosomes are small cylindrical ECM adhesion structures approximately 0.5 um in diameter. They contain focal contact proteins like vinculin and paxillin and are found primarily in malignant cells. They can also be found in normal cells such as macrophages and osteoclasts...
formation (along with Arp3, cortactin
Cortactin
Cortactin is a monomeric protein located in the cytoplasm of cells that can be activated by external stimuli to promote polymerization and rearrangement of the actin cytoskeleton, especially the actin cortex around the cellular periphery. It is present in all cell types...
, and Rho GTPases).
Gelsolin also inhibits apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
by stabilizing the mitochondria. Prior to cell death, mitochondria normally lose membrane potential
Membrane potential
Membrane potential is the difference in electrical potential between the interior and exterior of a biological cell. All animal cells are surrounded by a plasma membrane composed of a lipid bilayer with a variety of types of proteins embedded in it...
and become more permeable. Gelsolin can impede the release of cytochrome C
Cytochrome c
The Cytochrome complex, or cyt c is a small heme protein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is a highly soluble protein, unlike other cytochromes, with a solubility of about 100 g/L and is an...
, obstructing the signal amplification that would have led to apoptosis.
Actin can be cross-linked into a gel
Gel
A gel is a solid, jelly-like material that can have properties ranging from soft and weak to hard and tough. Gels are defined as a substantially dilute cross-linked system, which exhibits no flow when in the steady-state...
by actin cross-linking proteins. Gelsolin can turn this gel into a sol
Sol (colloid)
A sol is a colloidal suspension of very small solid particles in a continuous liquid medium. They are quite stable and show the Tyndall effect. Examples include blood, pigmented ink, and paint....
, hence the name gelsolin.
Organismal Relevance
Research in mice suggests that gelsolin, like other actin-severing proteins, is not expressed to a significant degree until after the early embryoEmbryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
nic stage—approximately 2 weeks in murine embryos. In adult specimens, however, gelsolin is particularly important in motile cells, such as blood platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
s. Mice with null gelsolin-coding genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
undergo normal embryonic development
Embryogenesis
Embryogenesis is the process by which the embryo is formed and develops, until it develops into a fetus.Embryogenesis starts with the fertilization of the ovum by sperm. The fertilized ovum is referred to as a zygote...
, 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
SequenceSequence (biology)
A sequence in biology is the one-dimensional ordering of monomers, covalently linked within in a biopolymer; it is also referred to as the primary structure of the biological macromolecule.-See also:* Protein sequence* DNA sequence...
comparisons indicate an evolution
Evolution
Evolution is any change across successive generations in the heritable characteristics of biological populations. Evolutionary processes give rise to diversity at every level of biological organisation, including species, individual organisms and molecules such as DNA and proteins.Life on Earth...
ary 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 repeat
Tandem repeat
Tandem repeats occur in DNA when a pattern of two or more nucleotides is repeated and the repetitions are directly adjacent to each other. -Example:An example would be:in which the sequence A-T-T-C-G is repeated three times.-Terminology:...
s have yet to be related to any known function of the actin-severing proteins, the superfamily
Superfamily
The term superfamily is used to describe several different concepts in different scientific fields:* Superfamily and Superfamily : a level of biological classification; redirects to Taxonomic rank...
appears to have evolved
Evolution
Evolution is any change across successive generations in the heritable characteristics of biological populations. Evolutionary processes give rise to diversity at every level of biological organisation, including species, individual organisms and molecules such as DNA and proteins.Life on Earth...
from an ancestral sequence
Sequence
In mathematics, a sequence is an ordered list of objects . Like a set, it contains members , and the number of terms is called the length of the sequence. Unlike a set, order matters, and exactly the same elements can appear multiple times at different positions in the sequence...
of 120 to 130 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
residues
Residue (chemistry)
In chemistry, residue is the material remaining after a distillation or an evaporation, or to a portion of a larger molecule, such as a methyl group. It may also refer to the undesired byproducts of a reaction....
.
Interactions
Gelsolin is a cytoplasmic, calcium-regulated, actin-modulating proteinProtein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that binds to the barbed ends of actin
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
filaments, preventing monomer
Monomer
A monomer is an atom or a small molecule that may bind chemically to other monomers to form a polymer; the term "monomeric protein" may also be used to describe one of the proteins making up a multiprotein complex...
exchange (end-blocking or capping). It can promote nucleation (the assembly of monomers into filaments), as well as sever existing filaments
Protein filament
In biology, a filament is a "long chain of proteins, such as those found in hair, muscle, or in flagella". They are often bundled together for strength and rigidity. Some cellular examples include:*Actin filaments*Microtubules*Intermediate filaments...
. In addition, this protein binds with high affinity to fibronectin
Fibronectin
Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans...
. Plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
gelsolin and cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
ic gelsolin are derived from a single gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
by alternate initiation sites and differential splicing
Splicing (genetics)
In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...
.
Gelsolin has been shown to interact
Protein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with VDAC1
VDAC1
Voltage-dependent anion-selective channel protein 1 is a protein that in humans is encoded by the VDAC1 gene.-Interactions:VDAC1 has been shown to interact with Gelsolin, BCL2-like 1, PRKCE, Bcl-2-associated X protein and DYNLT3.- External links :...
, Amyloid precursor protein
Amyloid precursor protein
Amyloid precursor protein is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export...
, Androgen receptor
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
and PTK2B
PTK2B
Protein tyrosine kinase 2 beta is an enzyme that in humans is encoded by the PTK2B gene.-Protein:-Interactions:PTK2B has been shown to interact with PTPN11, PTPN6, PITPNM1, Gelsolin, Src, GRIN2A, Ewing sarcoma breakpoint region 1, RB1CC1, TGFB1I1, NPHP1, BCAR1, FYN, DLG4, DLG3, DDEF2, Cbl gene, RAS...
.