Talin is a high-molecular-weight
cytoskeletal
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all Cell (biology), cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane ...
protein concentrated at regions of cell–substratum contact
and, in
lymphocytes
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), and ...
, at cell–cell contacts.
Discovered in 1983 by
Keith Burridge
Keith Burridge (born 1 July 1950) is a British researcher and Kenan distinguished Professor at the University of North Carolina at Chapel Hill.ISI Highly Cited ResearcheAn essay by: Professor Keith Burridgein-cites.com His research on focal adhe ...
and colleagues,
talin is a ubiquitous
cytosolic
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 ...
protein that is found in high concentrations in
focal adhesions. It is capable of linking
integrins
Integrins are transmembrane receptors that help cell–cell and cell– extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
to the
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 ...
cytoskeleton either directly or indirectly by interacting with
vinculin
In mammalian cells, vinculin is a membrane-cytoskeletal protein in focal adhesion plaques that is involved in linkage of integrin adhesion molecules to the actin cytoskeleton. Vinculin is a cytoskeletal protein associated with cell-cell and cell ...
and
α-actinin.
Also, talin-1 drives
extravasation
Extravasation is the leakage of a fluid out of its contained space into the surrounding area, especially blood or blood cells from vessels. In the case of inflammation, it refers to the movement of white blood cells through the capillary wall, ...
mechanism through engineered human
microvasculature in microfluidic systems. Talin-1 is involved in each part of extravasation affecting adhesion, trans-endothelial migration and the invasion stages.
Integrin receptors are involved in the attachment of adherent cells to the
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and bio ...
and of lymphocytes to other cells. In these situations, talin codistributes with concentrations of integrins in the
plasma membrane
The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...
.
Furthermore,
in vitro
''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...
binding studies suggest that integrins bind to talin, although with low affinity.
Talin also binds with high affinity to vinculin,
another cytoskeletal protein concentrated at points of
cell adhesion
Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as Cell_junction, cell junc ...
.
Finally, talin is a substrate for the calcium-ion activated
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...
,
calpain
A calpain (; , ) is a protein belonging to the family of calcium-dependent, non-lysosomal cysteine proteases ( proteolytic enzymes) expressed ubiquitously in mammals and many other organisms. Calpains constitute the C2 family of protease clan C ...
II,
which is also concentrated at points of cell–substratum contact.
Talin is a mechanosensitive protein. Its mechanical vulnerability
and cellular position bridging integrin receptors and the actin cytoskeleton make it a fundamental protein in
mechanotransduction
In cellular biology, mechanotransduction ('' mechano'' + '' transduction'') is any of various mechanisms by which cells convert mechanical stimulus into electrochemical activity. This form of sensory transduction is responsible for a number o ...
. Mechanical stretching of talin promotes vinculin binding.
Protein domains
Talin consists of a large
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy 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 t ...
rod domain that contains bundles of
alpha helices
An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix).
The alpha helix is the most common structural arrangement in the secondary structure of proteins. It is also the most extreme type of l ...
and an
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 amin ...
FERM (
band 4.1,
ezrin
Ezrin also known as cytovillin or villin-2 is a protein that in humans is encoded by the ''EZR'' gene.
Structure
The N-terminus of ezrin contains a FERM domain which is further subdivided into three subdomains. The C-terminus contains an ...
,
radixin
Radixin is a protein that in humans is encoded by the ''RDX'' gene.
Radixin is a cytoskeletal protein that may be important in linking actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoske ...
, and
moesin
Moesin is a protein that in humans is encoded by the ''MSN'' gene.
Moesin (for membrane-organizing extension spike protein) is a member of the ERM protein family which includes ezrin and radixin. ERM proteins appear to function as cross-linkers ...
) domain with three subdomains: F1, F2, and F3.
The F3 subdomain of the FERM domain contains the highest affinity integrin-binding site for
integrin
Integrins are transmembrane receptors that help cell–cell and cell–extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, o ...
β tails and is sufficient to activate integrins.
Middle domain
Structure
Talin also has a middle domain, which has a
structure
A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...
consisting of five
alpha helices
An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix).
The alpha helix is the most common structural arrangement in the secondary structure of proteins. It is also the most extreme type of l ...
that
fold into a bundle. It contains a vinculin
binding site
In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...
(VBS) composed of a
hydrophobic
In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, thu ...
surface spanning five
turn
To turn is to rotate, either continuously like a wheel turns on its axle, or in a finite motion changing an object's orientation. Turn may also refer to:
Sports and games
* Turn (game), a segment of a game
* Turn (poker), the fourth of five co ...
s of
helix
A helix (; ) is a shape like a cylindrical coil spring or the thread of a machine screw. It is a type of smooth space curve with tangent lines at a constant angle to a fixed axis. Helices are important in biology, as the DNA molecule is for ...
four.
Function
Activation of the VBS leads to the recruitment of vinculin to form a complex with the integrins which aids stable cell adhesion. Formation of the
complex
Complex commonly refers to:
* Complexity, the behaviour of a system whose components interact in multiple ways so possible interactions are difficult to describe
** Complex system, a system composed of many components which may interact with each ...
between VBS and vinculin requires prior unfolding of this middle domain: once released from the talin hydrophobic core, the VBS helix is then available to induce the 'bundle conversion'
conformational change
In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors.
A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or othe ...
within the vinculin head domain thereby displacing the intramolecular interaction with the vinculin tail, allowing vinculin to
bind
BIND () is a suite of software for interacting with the Domain Name System (DNS). Its most prominent component, named (pronounced ''name-dee'': , short for ''name Daemon (computing), daemon''), performs both of the main DNS server roles, acting ...
actin.
Talin carries mechanical force (of 7-10 piconewton) during cell adhesion. It also allows cells to measure extracellular rigidity, since cells in which talin is prevented from forming mechanical linkages can no longer distinguish whether they are on a soft or rigid surface. The actin binding site2 is shown to be the major site for sensing the extracellular matrix rigidity.
Recently Kumar ''et al''
combined cellular
electron cryo-tomography with
FRET
A fret is any of the thin strips of material, usually metal wire, inserted laterally at specific positions along the neck or fretboard of a stringed instrument. Frets usually extend across the full width of the neck. On some historical inst ...
based tension measurements and find that the regions of high talin tension within focal adhesion have highly aligned and linear underlying filamentous actin structures while regions of low talin tension have less well-aligned actin filaments.
Vinculin binding site
Function
Vinculin binding sites are
protein domains
In molecular biology, a protein domain is a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist of se ...
predominantly found in talin and talin-like molecules, enabling binding of vinculin to talin, stabilising integrin-mediated cell-matrix junctions. Talin, in turn, links integrins to the actin cytoskeleton.
Structure
The
consensus sequence
In molecular biology and bioinformatics, the consensus sequence (or canonical sequence) is the calculated sequence of most frequent residues, either nucleotide or amino acid, found at each position in a sequence alignment. It represents the result ...
for vinculin binding sites is LxxAAxxVAxxVxxLIxxA, with a
secondary structure
Protein secondary structure is the local spatial conformation of the polypeptide backbone excluding the side chains. The two most common Protein structure#Secondary structure, secondary structural elements are alpha helix, alpha helices and beta ...
prediction of four
amphipathic
In chemistry, an amphiphile (), or amphipath, is a chemical compound possessing both hydrophilic (''water-loving'', polar) and lipophilic (''fat-loving'', nonpolar) properties. Such a compound is called amphiphilic or amphipathic. Amphiphilic c ...
helices. The hydrophobic
residues that define the VBS are themselves 'masked' and are buried in the core of a series of helical bundles that make up the talin rod.
Activation of the integrin αIIbβ3
A structure–function analysis reported in 2007
provides a cogent structural model (see top right) to explain talin-dependent
integrin
Integrins are transmembrane receptors that help cell–cell and cell–extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, o ...
activation in three steps:
# The talin F3 domain (surface representation; colored by charge), freed from its autoinhibitory interactions in the full-length protein, becomes available for binding to the integrin.
#F3 engages the membrane-distal part of the
β3-integrin tail (in red), which becomes ordered, but the α–β integrin interactions that hold the integrin in the low-affinity conformation remain intact.
# In a subsequent step, F3 engages the membrane-proximal portion of the β3 tail while maintaining its membrane–distal interactions.
Human proteins containing this domain
TLN1;
TLN2;
See also
*
Actin-binding protein Actin-binding proteins (also known as ABPs) are proteins that bind to actin. This may mean ability to bind actin monomers, or polymers, or both.
Many actin-binding proteins, including α-actinin, β-spectrin, dystrophin, utrophin and fimbrin, do t ...
*
Merlin (protein)
Merlin (also called neurofibromin 2 or schwannomin) is a cytoskeletal protein. In humans, it is a tumor suppressor protein involved in neurofibromatosis type II. Sequence data reveal its similarity to the ERM protein family.
''Merlin'' is an a ...
an acronym for "Moesin-Ezrin-Radixin-Like Protein"
References
External links
MBInfo: TalinMBInfo: Talin activates IntegrinTalin-1UniProtKB/Swiss-Prot entr
Q9Y490Talin substrate for calpain– PMAP
The Proteolysis Map animation.
Talin-1Info with links in th
Cell Migration Gateway
Talin-2Info with links in th
Cell Migration Gateway
*
{{Immune receptors
Integral membrane proteins