Formins
Encyclopedia
Formins are a group of proteins that are involved in the polymerization
of actin
and associate with the fast-growing end (barbed end) of actin filaments. Most formins are Rho-GTPase effector proteins. Formins regulate the actin and microtubule cytoskeleton and are involved in various cellular functions such as cell polarity, cytokinesis, cell migration and SRF transcriptional activity. Formins are multidomain proteins
that interact
with diverse signalling molecule
s and cytoskeletal proteins, although some formins have been assigned functions within the nucleus
. Formins are characterised by the presence of three FH domains
(FH1, FH2 and FH3), although members of the formin family do not necessarily contain all three domains.
The proline
-rich FH1 domain mediates interactions
with a variety of proteins, including the actin-binding protein
profilin
, SH3
(Src homology 3) domain proteins, and WW domain
proteins. The actin nucleation-promoting activity of S. cerevisiae
formins has been localized to the FH2 domain. The FH2 domain is required for the self-association of formin proteins through the ability of FH2 domains to directly bind each other, and may also act to inhibit
actin polymerisation. The FH3 domain is less well conserved
and is required for directing formins to the correct intracellular
location, such the mitotic spindle
, or the projection tip during conjugation
. In addition, some formins can contain a GTPase
-binding domain (GBD) required for binding
to Rho small GTPases
, and a C-terminal conserved
DRF autoregulatory domain (Dia-autoregulatory domain) (DAD). The GBD domain is a bifunctional autoinhibitory domain that interact
s with and is regulated by activated Rho family members. Mammalian Drf3 contains a CRIB-like motif within its GBD for binding
to Cdc42
, which is required for Cdc42 to activate and guide Drf3 towards the cell cortex
where it remodels the actin skeleton. The DRF autoregulatory domain binds the N-terminal GTPase-binding domain; this link is broken when GTP-bound Rho binds to the GBD and activates the protein
. The addition of the DAD to mammalian cells
induces actin filament formation, stabilises microtubules, and activates serum-response mediated transcription
.. Another commonly found domain is an armadillo repeat region
(ARR) located in the FH3 domain.
The FH2 domain, has been shown by X-ray crystallography
to have an elongated, crescent shape containing three helical subdomains.
Formins also directly bind to microtubules via their FH2 domain. This interaction is important in promoting the capture and stabilization of a subset of microtubules oriented towards the leading edge of migrating cells. Formins also promote the capture of microtubules by the kinetochore
during mitosis
and for aligning microtubules along actin filaments.
Polymerization
In polymer chemistry, polymerization is a process of reacting monomer molecules together in a chemical reaction to form three-dimensional networks or polymer chains...
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...
and associate with the fast-growing end (barbed end) of actin filaments. Most formins are Rho-GTPase effector proteins. Formins regulate the actin and microtubule cytoskeleton and are involved in various cellular functions such as cell polarity, cytokinesis, cell migration and SRF transcriptional activity. Formins are multidomain proteins
Protein
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 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 diverse signalling molecule
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
s and cytoskeletal proteins, although some formins have been assigned functions within the nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
. Formins are characterised by the presence of three FH domains
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
(FH1, FH2 and FH3), although members of the formin family do not necessarily contain all three domains.
The proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
-rich FH1 domain mediates interactions
Protein interactions
Proteins can interact with many types of molecules. Such interactions are related to their function and are therefore an object of study in molecular biology, and of computational methods of prediction in bioinformatics.Protein interactions can be classified as:...
with a variety of proteins, including the actin-binding protein
Actin-binding protein
Actin-binding proteins are proteins that bind to actin. This may mean ability to bind actin monomers, or polymers, or both....
profilin
Profilin
Profilin is an actin-binding protein involved in the dynamic turnover and restructuring of the actin cytoskeleton. It is found in all eukaryotic organisms in most cells. Profilin is important for spatially and temporally controlled growth of actin microfilaments, which is an essential process in...
, SH3
SH3 domain
The SRC Homology 3 Domain is a small protein domain of about 60 amino acids residues first identified as a conserved sequence in the viral adaptor protein v-Crk and the non-catalytic parts of enzymes such as phospholipase and several cytoplasmic tyrosine kinases such as Abl and Src...
(Src homology 3) domain proteins, and WW domain
WW domain
The WW domain is a protein domain with two highly conserved tryptophans that binds proline-rich peptide motifs...
proteins. The actin nucleation-promoting activity of S. cerevisiae
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
formins has been localized to the FH2 domain. The FH2 domain is required for the self-association of formin proteins through the ability of FH2 domains to directly bind each other, and may also act to inhibit
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
actin polymerisation. The FH3 domain is less well conserved
Conserved sequence
In biology, conserved sequences are similar or identical sequences that occur within nucleic acid sequences , protein sequences, protein structures or polymeric carbohydrates across species or within different molecules produced by the same organism...
and is required for directing formins to the correct intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
location, such the mitotic spindle
Mitotic spindle
In cell biology, the spindle fibers are the structure that separates the chromosomes into the daughter cells during cell division. It is part of the cytoskeleton in eukaryotic cells...
, or the projection tip during conjugation
Conjugation
Conjugation or conjugate may refer to:* Conjugation , the modification of a verb from its basic form* Conjugate , used to rationalize the denominator of a fraction...
. In addition, some formins can contain a GTPase
GTPase
GTPases are a large family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate . The GTP binding and hydrolysis takes place in the highly conserved G domain common to all GTPases.-Functions:...
-binding domain (GBD) required for binding
Binding (molecular)
Molecular binding is an attractive interaction between two molecules which results in a stable association in which the molecules are in close proximity to each other...
to Rho small GTPases
Rho GTPase
A Rho GTPase may refer to:*Any member of the Rho family of GTPases*The members of the Rho family of GTPases belonging to the Rho subclass*RhoA, the most-studied member of the Rho subclass of the Rho family of GTPases...
, and a C-terminal conserved
Conserved sequence
In biology, conserved sequences are similar or identical sequences that occur within nucleic acid sequences , protein sequences, protein structures or polymeric carbohydrates across species or within different molecules produced by the same organism...
DRF autoregulatory domain (Dia-autoregulatory domain) (DAD). The GBD domain is a bifunctional autoinhibitory domain that 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...
s with and is regulated by activated Rho family members. Mammalian Drf3 contains a CRIB-like motif within its GBD for binding
Binding (molecular)
Molecular binding is an attractive interaction between two molecules which results in a stable association in which the molecules are in close proximity to each other...
to Cdc42
CDC42
Cell division control protein 42 homolog also known as CDC42 is a protein involved in regulation of the cell cycle. In humans, CDC42 is encoded by the CDC42 gene.- Function :...
, which is required for Cdc42 to activate and guide Drf3 towards the cell cortex
Cell cortex
The cell cortex is a specialized layer of cytoplasm on the inner face of the plasma membrane that functions as a mechanical support of the plasma membrane. In animal cells it is an actin-rich layer responsible for movements of the cell surface. In plant cells, the cell cortex is reinforced by...
where it remodels the actin skeleton. The DRF autoregulatory domain binds the N-terminal GTPase-binding domain; this link is broken when GTP-bound Rho binds to the GBD and activates the protein
Protein
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...
. The addition of the DAD to mammalian cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
induces actin filament formation, stabilises microtubules, and activates serum-response mediated transcription
Transcription
Transcription may refer to:*Transcription , a business which converts speech into a written or electronic text document*Transcription , software which helps convert speech into text transcript...
.. Another commonly found domain is an armadillo repeat region
Armadillo repeats
Armadillo repeats are named after the β-catenin-like Armadillo protein of the fruit fly Drosophila. These repeats are about 40 amino acids long and proteins that contain them have many tandemly repeated copies. Each Armadillo repeat is composed of a pair of alpha helices that form a hairpin...
(ARR) located in the FH3 domain.
The FH2 domain, has been shown by X-ray crystallography
X-ray crystallography
X-ray crystallography is a method of determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and causes the beam of light to spread into many specific directions. From the angles and intensities of these diffracted beams, a crystallographer can produce a...
to have an elongated, crescent shape containing three helical subdomains.
Formins also directly bind to microtubules via their FH2 domain. This interaction is important in promoting the capture and stabilization of a subset of microtubules oriented towards the leading edge of migrating cells. Formins also promote the capture of microtubules by the kinetochore
Kinetochore
The kinetochore is the protein structure on chromatids where the spindle fibers attach during cell division to pull sister chromatids apart....
during mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
and for aligning microtubules along actin filaments.