Talin is a high-molecular-weight
cytoskeletal
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compo ...
protein concentrated at regions of cell–substratum contact
and, in
lymphocytes, 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 adhesi ...
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
In cell biology, focal adhesions (also cell–matrix adhesions or FAs) are large macromolecular assemblies through which mechanical force and regulatory signals are transmitted between the extracellular matrix (ECM) and an interacting cell. More ...
. It is capable of linking
integrins
Integrins are transmembrane receptors that facilitate 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 ov ...
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
Actinin is a microfilament protein. Alpha-actinin-1 is necessary for the attachment of actin myofilaments to the Sarcomere, Z-lines in Skeletal muscle, skeletal muscle cells, and to the Smooth muscle tissue, dense bodies in smooth muscle cells. The ...
.
Also, talin-1 drives extravasation 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, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide s ...
and of lymphocytes to other cells. In these situations, talin codistributes with concentrations of integrins in the
plasma membrane.
Furthermore,
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology ...
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.
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 catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
,
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. 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, 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 ...
rod domain that contains bundles of
alpha 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 ...
and an
N-terminal FERM (band 4.1, ezrin, radixin, and moesin) 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 facilitate 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, ...
β tails and is sufficient to activate integrins.
Middle domain
Structure
Talin also has a middle domain, which has a
structure consisting of five
alpha 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 ...
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 physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, t ...
surface spanning five
turns of
helix
A helix () is a shape like a corkscrew or spiral staircase. 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 formed as two intertwined helic ...
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 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''), performs both of the main DNS server roles, acting as an authoritative ...
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 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 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 for vinculin binding sites is LxxAAxxVAxxVxxLIxxA, with a
secondary structure
Protein secondary structure is the three dimensional conformational isomerism, form of ''local segments'' of proteins. The two most common Protein structure#Secondary structure, secondary structural elements are alpha helix, alpha helices and beta ...
prediction of four
amphipathic
An amphiphile (from the Greek αμφις amphis, both, and φιλíα philia, love, friendship), or amphipath, is a chemical compound possessing both hydrophilic (''water-loving'', polar) and lipophilic (''fat-loving'') properties. Such a compoun ...
helices. The hydrophobic
residue
Residue may refer to:
Chemistry and biology
* An amino acid, within a peptide chain
* Crop residue, materials left after agricultural processes
* Pesticide residue, refers to the pesticides that may remain on or in food after they are applied ...
s 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 recently
provides a cogent structural model (see top right) to explain talin-dependent
integrin
Integrins are transmembrane receptors that facilitate 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, ...
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
Talin-1 is a protein that in humans is encoded by the ''TLN1'' gene. Talin-1 is ubiquitously expressed, and is localized to costamere structures in cardiac and skeletal muscle cells, and to focal adhesions in smooth muscle and non-muscle cells. Tal ...
;
TLN2
Talin 2 is a protein in humans that is encoded by the TLN2 gene. It belongs to the talin protein family.
This gene encodes a protein related to talin 1, a cytoskeletal protein that plays a significant role in the assembly of actin filaments. Tali ...
;
See also
*
Actin-binding protein
*
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.
The name "merlin" is ...
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
The Proteolysis MAP (PMAP) is an integrated web resource focused on proteases.
Rationale
PMAP is to aid the protease researchers in reasoning about proteolytic networks and metabolic pathways.
History and funding
PMAP was originally created ...
animation.
Talin-1Info with links in th
Cell Migration Gateway
Talin-2Info with links in th
Cell Migration Gateway
*
{{Immune receptors
Integral membrane proteins