Gelsolin is an
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...
-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-1 is a 92.5 kDa tissue-specific actin-binding protein associated with the actin core bundle of the brush border. Villin-1 is encoded by the ''VIL1'' gene. Villin-1 contains multiple gelsolin-like domains capped by a small (8.5 kDa) "headp ...
superfamily, as it severs with nearly 100% efficiency.
Cellular gelsolin, found within the
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
and
mitochondria
A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
,
has a closely related secreted form,
Plasma gelsolin
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 ea ...
, that contains an additional 24 AA N-terminal extension.
Plasma gelsolin's ability to sever
actin filaments
Microfilaments, also called actin filaments, are protein filaments in the cytoplasm of eukaryotic cells that form part of the cytoskeleton. They are primarily composed of polymers of actin, but are modified by and interact with numerous other pr ...
helps the body recover from disease and injury that leaks cellular actin into the blood. Additionally it plays important roles in host
innate immunity
The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...
, activating
macrophages
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
and localizing of
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
.
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
The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a g ...
, flanked by two
α-helices
The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...
, one positioned perpendicular with respect to the strands and one positioned parallel. The β-sheets of the three
N-terminal
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
subdomains (S1-S3) join to form an extended β-sheet, as do the β-sheets of the
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
subdomains (S4-S6).
Regulation
Among the
lipid
Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...
-binding actin regulatory proteins, gelsolin (like
cofilin
ADF/cofilin is a family of actin-binding proteins associated with the rapid depolymerization of actin microfilaments that give actin its characteristic dynamic instability. This dynamic instability is central to actin's role in muscle contractio ...
) preferentially binds polyphosphoinositide (PPI).
The binding sequences in gelsolin closely resemble the motifs in the other PPI-binding proteins.
Gelsolin's activity is stimulated by calcium ions (Ca
2+).
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 Ca
2+ 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 or PtdIns(4,5)''P''2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)''P''2 is enriched at the plasma membrane where it is a substrate for a number of ...
(PIP
2), a PPI. This is a two step process. Firstly, (PIP
2) binds to S2 and S3, inhibiting gelsolin from actin side binding. Then, (PIP
2) binds to gelsolin’s S1, preventing gelsolin from severing actin, although (PIP
2) does not bind directly to gelsolin's actin-binding site.
Gelsolin's severing of actin, in contrast to the severing of
microtubules
Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nm and have an inner diameter between 11 an ...
by
katanin Katanin is a microtubule-severing AAA protein. It is named after the Japanese sword called a katana. Katanin is a heterodimeric protein first discovered in sea urchins. It contains a 60 Dalton (unit), kDa ATPase Protein subunit, subunit, encoded by ...
, does not require any extra energy input.
Cellular function
As an important actin regulator, gelsolin plays a role in
podosome
Podosomes are conical, actin-rich structures found on the outer surface of the plasma membrane of animal cells. Their size ranges from approximately 0.5 µm to 2.0 µm in diameter. While usually situated on the periphery of the cellular ...
formation (along with Arp3,
cortactin
Cortactin (from "''cortical actin'' binding protein") 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 c ...
, and Rho GTPases).
Gelsolin also inhibits
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
by stabilizing the
mitochondria
A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
.
Prior to cell death, mitochondria normally lose
membrane potential
Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. That is, there is a difference in the energy required for electric charges ...
and become more permeable. Gelsolin can impede the release of
cytochrome C
The cytochrome complex, or cyt ''c'', is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins and plays a major role in cell apoptosis. Cytochrome c is hig ...
, obstructing the signal amplification that would have led to apoptosis.
Actin can be cross-linked into a
gel
A gel is a semi-solid 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, although the liquid phase may still dif ...
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
embryo
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...
nic stage—approximately 2 weeks in
murine
The Old World rats and mice, part of the subfamily Murinae in the family Muridae, comprise at least 519 species. Members of this subfamily are called murines. In terms of species richness, this subfamily is larger than all mammal families excep ...
embryos.
In adult specimens, however, gelsolin is particularly important in motile cells, such as blood
platelet
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
s. Mice with null gelsolin-coding
genes
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
undergo normal
embryonic development
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...
, 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
In mathematics, a sequence is an enumerated collection of objects in which repetitions are allowed and order matters. Like a set, it contains members (also called ''elements'', or ''terms''). The number of elements (possibly infinite) is calle ...
comparisons indicate an
evolution
Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...
ary relationship between gelsolin,
villin
Villin-1 is a 92.5 kDa tissue-specific actin-binding protein associated with the actin core bundle of the brush border. Villin-1 is encoded by the ''VIL1'' gene. Villin-1 contains multiple gelsolin-like domains capped by a small (8.5 kDa) "headp ...
,
fragmin, and
severin.
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
In molecular biology, ADF-H domain (actin-depolymerising factor homology domain) is an approximately 150 amino acid motif that is present in three phylogenetically distinct classes of eukaryotic actin-binding proteins.
*ADF/cofilins, which incl ...
, forming a superfamily (). The
family
Family (from la, familia) is a Social group, group of people related either by consanguinity (by recognized birth) or Affinity (law), affinity (by marriage or other relationship). The purpose of the family is to maintain the well-being of its ...
appears to have
evolved
Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation t ...
from an ancestral
sequence
In mathematics, a sequence is an enumerated collection of objects in which repetitions are allowed and order matters. Like a set, it contains members (also called ''elements'', or ''terms''). The number of elements (possibly infinite) is calle ...
of 120 to 130
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
residues.
Asgard archaea encode many functional gelsolins.
Interactions
Gelsolin is a
cytoplasmic
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. Th ...
, calcium-regulated, actin-modulating
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that binds to the barbed ends of
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...
filaments, preventing
monomer
In chemistry, a monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization.
Classification
Mo ...
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
Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...
.
Plasma gelsolin
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 ea ...
and cytoplasmic gelsolin are derived from a single
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
by alternate initiation sites and differential
splicing.
Gelsolin has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
*
Amyloid precursor protein
Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many biological tissue, tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator ...
,
*
Androgen receptor
The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone in th ...
,
*
PTK2B
Protein tyrosine kinase 2 beta is an enzyme that in humans is encoded by the ''PTK2B'' gene.
Function
This gene encodes a cytoplasmic protein tyrosine kinase that is involved in calcium-induced regulation of ion channels and activation of the ...
,
and
*
VDAC1
Voltage-dependent anion-selective channel 1 (VDAC-1) is a beta barrel protein that in humans is encoded by the ''VDAC1'' gene located on chromosome 5. It forms an ion channel in the outer mitochondrial membrane (OMM) and also the outer cell membra ...
.
See also
*
Plasma gelsolin
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 ea ...
*
Cortactin
Cortactin (from "''cortical actin'' binding protein") 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 c ...
*
Villin
Villin-1 is a 92.5 kDa tissue-specific actin-binding protein associated with the actin core bundle of the brush border. Villin-1 is encoded by the ''VIL1'' gene. Villin-1 contains multiple gelsolin-like domains capped by a small (8.5 kDa) "headp ...
*
Supervillin
Supervillin is a protein that in humans is encoded by the ''SVIL'' gene.
Function
This gene encodes a bipartite protein with distinct amino- and carboxy-terminal domains. The amino-terminus contains nuclear localization signals and the carboxy ...
*
Finnish type amyloidosis
References
External links
*
{{PDB_Gallery, geneid=2934
* http://www.bioaegistherapeutics.com
Proteins