IL2 receptor
Encyclopedia
The interleukin-2 receptor (IL-2R) is a heterotrimeric
protein expressed on the surface of certain immune cells, such as lymphocyte
s, that binds and responds to a cytokine
called IL-2. Three protein chains (α, β and γ) are non-covalently associated to form the IL-2R. The α and β chains are involved in binding IL-2, while signal transduction
following cytokine interaction is carried out by the γ-chain, along with the β subunit. The β and γ chains of the IL-2R are members of the type I cytokine receptor
family.
receptor to be described and characterized by Kendall Smith and his team at Dartmouth Medical School. It was found to have a high affinity binding site and is expressed by antigen-activated T lymphocytes (T cell
s). Radiolabeled IL-2 concentrations found to saturate these sites (e.g. 1-100 pM) were identical to those determined to promote T cell proliferation
. Subsequently, the three distinct receptor chains, termed alpha (α
), beta (β
) and gamma (γ) were identified. The high affinity of IL-2 binding is created by a rapid association rate (k = 107/M/s) contributed by the alpha chain, and a relatively slow dissociation rate (k' = 10−4/s) contributed by the beta and gamma chains.
revealed that the alpha chain of the IL-2R can bind to the beta chain before receptor interaction with IL-2, and that the IL-2Rα/β heterodimer formed has a faster association rate and a slower dissociation rate when binding IL-2 versus either chain alone. The gamma chain alone has a very weak affinity for IL-2 (Kd > 700 uM), but after IL-2 is bound to the α/β heterodimer, the gamma chain becomes recruited to the IL2/IL2R complex to form a very stable macromolecular quaternary ligand/receptor complex. These data were recently confirmed and extended by energetics experiments using Isothermal Titration Calorimetry
and Multi-Angle Light Scattering
.
The 3-dimensional structure of the three IL-2R chains binding IL-2 was determined by crystallization of the complex followed by X-ray diffraction.
The sites on the IL-2 molecule that interact with the three receptor chains do not overlap, except for a small but significant region. The IL-2 molecule is composed of four antiparallel alpha helices
and it is held between the beta and gamma chains, which converge to form a Y shape; IL-2 is held in the fork of the Y. The other side of the IL-2 molecule binds to the IL-2R alpha chain. The alpha chain itself does not contact either beta or gamma chain of the IL-2R. Following the binding of IL-2, the beta chain undergoes a conformational change that evidently increases its affinity for the gamma chain, thereby attracting it to form a stable quaternary molecular complex.
The alpha chain is called CD25
.
and extend into the cell, thereby delivering biochemical signals to the cell interior. The alpha chain does not participate in signaling, but the beta chain is complexed with an enzyme
called Janus kinase 1
(JAK1), that is capable of adding phosphate groups to molecules. Similarly the gamma chain complexes with another tyrosine kinase
called JAK
3. These enzymes are activated by IL-2 binding to the external domains of the IL-2R. As a consequence, three intracellular signaling pathways are initiated, the MAP kinase pathway
, the Phosphoinositide 3-kinase
(PI3K) pathway, and the JAK-STAT pathway.
when a critical number of IL-2Rs have been triggered. Given that the half-time for internalization of IL-2 occupied IL-2Rs is ~ 15 minutes, it is possible to calculate the number of triggered IL-2Rs necessary. Thus, the critical number of triggered IL-2Rs is ~ 30,000. In as much that the mean number of high affinity IL-2Rs on antigen-activated T cells is only ~ 1,000, it appears that new receptors must be synthesized before the cell makes the quantal, all-or-none decision to divide. Accordingly, a mean of at least 11 hours of IL-2/IL-2R interaction are necessary before a cell decides to undergo DNA replication.
Until recently, the intracellular molecules activated by the IL-2R at the cell membrane that are responsible for promoting cell cycle progression were obscure. However, early on it was shown that IL-2Rs triggered the expression of cyclin
D2 and cyclin D3. Now it is known that the STAT
5a/b molecules activated by the IL-2R via the JAK1/3 kinases promote the transcriptional activation of the D cyclins. As well, via the activation of the PI3K pathway, an inhibitor of cyclin-D/CDK activity (p27) is targeted for degradation. Both of these biochemical events, as well as others activated via the IL-2R ultimately promote progression through G1 of the cell cycle and through the G1 restriction point, thereby triggering the onset of DNA synthesis and replication.
The IL2R also signals negative feedback loops that function to inhibitIL-2 gene expression. These loops either shut down signaling via the T cell antigen receptor by activating the expression of CTLA-4, or by activating the expression of FOXP3, which as a negative regulator of IL-2 transcription operates at the level of the IL-2 promoter.
Other recent data indicate that T cells that express FOXP3 can suppress other T cells by binding IL-2 via the high affinity IL-2R, and followed by internalization of the quaternary IL-2/IL-2R complex, degrade IL-2. Thus, the concentration of IL-2 available determines the tempo, magnitude and extent of T cell immune responses.
and daclizumab
are used in conjunction with other drugs to prevent immune rejection of transplants
.
Trimer (biochemistry)
In biochemistry, a trimer is a macromolecular complex formed by three, usually non-covalently bound, macromolecules like proteins or nucleic acids. A homo-trimer would be formed by three identical molecules. A hetero-trimer would be formed by three different macromolecules. Collagen is an example...
protein expressed on the surface of certain immune cells, such as lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s, that binds and responds to a cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
called IL-2. Three protein chains (α, β and γ) are non-covalently associated to form the IL-2R. The α and β chains are involved in binding IL-2, while signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
following cytokine interaction is carried out by the γ-chain, along with the β subunit. The β and γ chains of the IL-2R are members of the type I cytokine receptor
Type I cytokine receptor
Type I cytokine receptors are transmembrane receptors expressed on the surface of cells that recognize and respond to cytokines with four α-helical strands. These receptors are also known under the name hemopoietin receptors, and share a common amino acid motif in the extracellular portion...
family.
Discovery and characterization
The IL-2 receptor (IL-2R) was the first interleukinInterleukin
Interleukins are a group of cytokines that were first seen to be expressed by white blood cells . The term interleukin derives from "as a means of communication", and "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes"...
receptor to be described and characterized by Kendall Smith and his team at Dartmouth Medical School. It was found to have a high affinity binding site and is expressed by antigen-activated T lymphocytes (T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s). Radiolabeled IL-2 concentrations found to saturate these sites (e.g. 1-100 pM) were identical to those determined to promote T cell proliferation
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
. Subsequently, the three distinct receptor chains, termed alpha (α
IL2RA
Interleukin-2 receptor alpha chain is a protein that in humans is encoded by the IL2RA gene.Infection by the protozoan Trypanosoma cruzi causes Chagas disease, characterized by a reduction in the amount of IL2RA expressed on the surface of immune cells...
), beta (β
IL2RB
Interleukin-2 receptor subunit beta is a protein that in humans is encoded by the IL2RB gene.-Interactions:IL2RB has been shown to interact with HGS, Janus kinase 1, CISH and SHC1.-Further reading:...
) and gamma (γ) were identified. The high affinity of IL-2 binding is created by a rapid association rate (k = 107/M/s) contributed by the alpha chain, and a relatively slow dissociation rate (k' = 10−4/s) contributed by the beta and gamma chains.
Structure-activity relationships of the IL-2/IL-2R interaction
Detailed experiments over a decade (1990s) using a rigorous reductionist approach with isolated purified receptor chains and Surface plasmon resonanceSurface plasmon resonance
The excitation of surface plasmons by light is denoted as a surface plasmon resonance for planar surfaces or localized surface plasmon resonance for nanometer-sized metallic structures....
revealed that the alpha chain of the IL-2R can bind to the beta chain before receptor interaction with IL-2, and that the IL-2Rα/β heterodimer formed has a faster association rate and a slower dissociation rate when binding IL-2 versus either chain alone. The gamma chain alone has a very weak affinity for IL-2 (Kd > 700 uM), but after IL-2 is bound to the α/β heterodimer, the gamma chain becomes recruited to the IL2/IL2R complex to form a very stable macromolecular quaternary ligand/receptor complex. These data were recently confirmed and extended by energetics experiments using Isothermal Titration Calorimetry
Isothermal Titration Calorimetry
Isothermal titration calorimetry is a physical technique used to determine the thermodynamic parameters of interactions in solution. It is most often used to study the binding of small molecules to larger macromolecules .-Thermodynamic measurements:ITC is a quantitative technique that can...
and Multi-Angle Light Scattering
Scattering
Scattering is a general physical process where some forms of radiation, such as light, sound, or moving particles, are forced to deviate from a straight trajectory by one or more localized non-uniformities in the medium through which they pass. In conventional use, this also includes deviation of...
.
The 3-dimensional structure of the three IL-2R chains binding IL-2 was determined by crystallization of the complex followed by X-ray diffraction.
The sites on the IL-2 molecule that interact with the three receptor chains do not overlap, except for a small but significant region. The IL-2 molecule is composed of four antiparallel alpha helices
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
and it is held between the beta and gamma chains, which converge to form a Y shape; IL-2 is held in the fork of the Y. The other side of the IL-2 molecule binds to the IL-2R alpha chain. The alpha chain itself does not contact either beta or gamma chain of the IL-2R. Following the binding of IL-2, the beta chain undergoes a conformational change that evidently increases its affinity for the gamma chain, thereby attracting it to form a stable quaternary molecular complex.
The alpha chain is called CD25
CD25
CD25 is the alpha chain of the IL-2 receptor. It is a type I transmembrane protein present on activated T cells, activated B cells, some thymocytes, myeloid precursors, and oligodendrocytes that associates with CD122 to form a heterodimer that can act as a high-affinity receptor for IL-2.CD25 is...
.
Signaling
The three IL-2 receptor chains span the cell membraneCell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
and extend into the cell, thereby delivering biochemical signals to the cell interior. The alpha chain does not participate in signaling, but the beta chain is complexed with an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
called Janus kinase 1
Jak
Jak may refer to:*JAK, Jazakomu Allahu Khayran *JAK members bank, a Swedish interest-free bank*Janus kinase, an intracellular signaling molecule; component of the JAK-STAT signal system...
(JAK1), that is capable of adding phosphate groups to molecules. Similarly the gamma chain complexes with another tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
called JAK
Jak
Jak may refer to:*JAK, Jazakomu Allahu Khayran *JAK members bank, a Swedish interest-free bank*Janus kinase, an intracellular signaling molecule; component of the JAK-STAT signal system...
3. These enzymes are activated by IL-2 binding to the external domains of the IL-2R. As a consequence, three intracellular signaling pathways are initiated, the MAP kinase pathway
MAPK/ERK pathway
The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a growth factor binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a...
, the Phosphoinositide 3-kinase
Phosphoinositide 3-kinase
Phosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...
(PI3K) pathway, and the JAK-STAT pathway.
T cell proliferation
Once IL-2 binds to the external domains of the IL-2R and the cytoplasmic domains are engaged, signaling continues until the IL-2/IL-2R complex is internalized and degraded. However, each cell only decides to make the irrevocable commitment to replicate its DNA and undergo mitosis and cytokinesisCytokinesis
Cytokinesis is the process in which the cytoplasm of a single eukaryotic cell is divided to form two daughter cells. It usually initiates during the late stages of mitosis, and sometimes meiosis, splitting a binucleate cell in two, to ensure that chromosome number is maintained from one generation...
when a critical number of IL-2Rs have been triggered. Given that the half-time for internalization of IL-2 occupied IL-2Rs is ~ 15 minutes, it is possible to calculate the number of triggered IL-2Rs necessary. Thus, the critical number of triggered IL-2Rs is ~ 30,000. In as much that the mean number of high affinity IL-2Rs on antigen-activated T cells is only ~ 1,000, it appears that new receptors must be synthesized before the cell makes the quantal, all-or-none decision to divide. Accordingly, a mean of at least 11 hours of IL-2/IL-2R interaction are necessary before a cell decides to undergo DNA replication.
Until recently, the intracellular molecules activated by the IL-2R at the cell membrane that are responsible for promoting cell cycle progression were obscure. However, early on it was shown that IL-2Rs triggered the expression of cyclin
Cyclin
Cyclins are a family of proteins that control the progression of cells through the cell cycle by activating cyclin-dependent kinase enzymes.- Function :...
D2 and cyclin D3. Now it is known that the STAT
STAT
STAT may mean:*STAT protein, the Signal Transducers and Activators of Transcription protein*Special Tertiary Admissions Test, a set of tests aimed at assessing the critical reasoning abilities of university applicants who lack other formal qualifications...
5a/b molecules activated by the IL-2R via the JAK1/3 kinases promote the transcriptional activation of the D cyclins. As well, via the activation of the PI3K pathway, an inhibitor of cyclin-D/CDK activity (p27) is targeted for degradation. Both of these biochemical events, as well as others activated via the IL-2R ultimately promote progression through G1 of the cell cycle and through the G1 restriction point, thereby triggering the onset of DNA synthesis and replication.
The IL2R also signals negative feedback loops that function to inhibitIL-2 gene expression. These loops either shut down signaling via the T cell antigen receptor by activating the expression of CTLA-4, or by activating the expression of FOXP3, which as a negative regulator of IL-2 transcription operates at the level of the IL-2 promoter.
Other recent data indicate that T cells that express FOXP3 can suppress other T cells by binding IL-2 via the high affinity IL-2R, and followed by internalization of the quaternary IL-2/IL-2R complex, degrade IL-2. Thus, the concentration of IL-2 available determines the tempo, magnitude and extent of T cell immune responses.
Clinical implications
Drugs that inhibit IL-2 receptors, such as basiliximabBasiliximab
Basiliximab is a chimeric mouse-human monoclonal antibody to the α chain of the IL-2 receptor of T cells. It is used to prevent rejection in organ transplantation, especially in kidney transplants...
and daclizumab
Daclizumab
Daclizumab is a therapeutic humanized monoclonal antibody to the alpha subunit of the IL-2 receptor of T cells. It is used to prevent rejection in organ transplantation, especially in kidney transplants....
are used in conjunction with other drugs to prevent immune rejection of transplants
Transplant rejection
Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after...
.