INTEGRINS BIDIRECTIONAL ALLOSTERIC SIGNALING MACHINES PDF

The exception is the beta-4 subunit, which has a cytoplasmic domain of 1, amino acids, one of the largest of any membrane protein. Beta subunits have four cysteine -rich repeated sequences. Integrins can be categorized in multiple ways. Integrins carrying this domain either bind to collagens e. In both cases, the A-domains carry up to three divalent cation binding sites. One is permanently occupied in physiological concentrations of divalent cations, and carries either a calcium or magnesium ion, the principal divalent cations in blood at median concentrations of 1.

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Integrins The inside-out signaling of integrins regulates the ligand-binding affinity of the cell surface receptors in response to changes in the environment for cell survival. Download PDF A living cell is constantly interacting with its environment to strive, and cell surface receptors play a vital role in mediating these interactions.

Integrins are the major metazoan receptors. By regulating cell-extracellular matrix contact, cell-cell adhesion and cell-pathogen interaction, integrins take part in a wide-range of biological processes, including development, angiogenesis, immune response, cancer and hemostasis, etc.

The name of integrin inherently means to integrate the extracellular and intracellular environments. There comes the most important aspect of their function: the bidirectional signaling across the plasma membrane. On the other hand, integrins are often expressed on the cell surface in a default low-affinity ligand-binding conformation. When cells become activated, for example by cytokine, integrins are rapidly activated in response to cellular stimulation within the cytoplasm.

They undergo large conformational changes, resulting in a dramatic affinity increase for ligand binding. This regulation of integrin activity is essential because inappropriate integrin activation in blood platelets, for instance, results in thrombosis 1 , 2 , 3.

Dissociation of the two tails by signals within the cell subsequently triggers conformational changes, activating integrins 2 , 3. A 2 residue long cytoplasmic protein, talin, is the key regulator of integrin affinity. Talin is composed of an N-terminal globular head, an extended rod of largely helical bundles, and followed by an actin-binding motif. Therefore, talin also plays a key adaptor role by linking the extracellular matrix to the cytoskeleton.

Figure 1 A Integrin activation. Left panel: both integrin and talin are in an inactivated state. The tails of two integrin subunits are close to each other. The extracellular domains of integrin are in low-affinity conformation for ligand.

Right panel: The RS domain of talin is relieved from talin-F3 domain. This leads to integrin activation. B Pull-push mechanism of talin activation. This gives a dual inhibition of talin activity. Right panel: PIP2-enriched membrane offers much stronger binding to pull the talin-F2F3 domains to membrane. Full size image Due to the fact that integrin activation has to be strictly controlled, the activity of talin itself is also tightly regulated. NMR studies have revealed an auto-inhibitory interaction between the FERM domain and the large C-terminal rod domain residues , termed talin-R.

This inhibition can be disrupted by talin activator, phosphotidylinositol 4,5-bisphosphate PIP2 A paper recently published in Cell Research by Song et al. Song et al. This structure unexpectedly reveals a dual inhibitory topology for talin. First, talin-RS binds to the F3 domain with no apparent contacts with F2. On the same face, talin-RS exposes a substantially negatively charged surface, which disfavors the complex docking on the membrane Figure 1B , left panel.

This crystallographic observation led the authors to explore an extremely intriguing question: how could talin be activated by PIP2 but not other lipids that are also found on the inner surface of the plasma membrane, such as POPS 1-palmitoyloleoyl-sn-glycerol[phospho-L-tidylserine] and POPC 1-palmitoyloleoyl-sn-glycerolphosphochoine?

In a broad sense, the authors may provide a new paradigm of a mechanism by which the dynamic surface chemical environment changes of cellular membrane regulate signal transduction through membrane.

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Integrins Bidirectional, Allosteric Signaling Machines

Integrins The inside-out signaling of integrins regulates the ligand-binding affinity of the cell surface receptors in response to changes in the environment for cell survival. Download PDF A living cell is constantly interacting with its environment to strive, and cell surface receptors play a vital role in mediating these interactions. Integrins are the major metazoan receptors. By regulating cell-extracellular matrix contact, cell-cell adhesion and cell-pathogen interaction, integrins take part in a wide-range of biological processes, including development, angiogenesis, immune response, cancer and hemostasis, etc. The name of integrin inherently means to integrate the extracellular and intracellular environments. There comes the most important aspect of their function: the bidirectional signaling across the plasma membrane. On the other hand, integrins are often expressed on the cell surface in a default low-affinity ligand-binding conformation.

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Integrins: bidirectional, allosteric signaling machines.

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