9/21/2023 0 Comments Affinity photo 1.7 vs 1.65![]() In the second step the IL-13:IL-13Rα1 complex recruits the IL-4Rα subunit into the complex. IL-13 binds first to the IL-13Rα1 subunit the affinity of IL-13 to IL-4Rα is below detection limit (app. (b) For IL-13 the order of the binding events is reversed. K D ~ 1.5 – 2 μM) is recruited into the complex. First, IL-4 is recruited to the membrane by its high-affinity subunit IL-4Rα second, either one of the two low affinity subunits IL-13Rα1 (apparent K D ~ 1 μM) or γ c (app. (a) The binding of IL-4 to its cellular receptor follows a two-step sequential binding mechanism. Sequential binding mechanism in the IL-4/-13 receptor activation. The γ c receptor subunit is shared among the cytokines IL-2, -4, -7, -9, -15 and -21, whereas the IL-13Rα1 subunit is exclusively used by IL-4 and -13. This intermediate ligand receptor complex then recruits one of two possible low-affinity receptor subunits, the common gamma chain (γ c) or the IL-13Rα1 chain, into the functional hetero-trimeric complex to initiate signalling. Signal transduction of IL-4 is mediated by a sequential binding process, initiated first by binding of IL-4 to its high-affinity single membrane spanning receptor chain IL-4Rα (Fig. Therefore, IL-4 plays a key role in the development and progression of allergic hypersensitivity. Activated T H2 cells play a triggering role in the activation and/or recruitment of IgE antibody-producing B cells, mast cells and eosinophils, which are all involved in allergic inflammation. Furthermore, it stimulates the expression of adhesion molecules such as VCAM-1 and chemokines such as eotaxin-1, -2 and -3. IL-4 induces the differentiation of T-helper cells to a type 2 (T H2) cytokine-producing phenotype and the class switching to IgE and IgG4. Interleukin 4 (IL-4) is a pleiotropic cytokine that plays a major regulatory role in the immune system. This limited specificity is, however, not accompanied by low binding affinities. Understanding how proteins generate affinity and specificity is essential as more and more growth factor receptor families show promiscuous binding to their respective ligands. An interface formed by several interaction clusters/binding hot-spots allows for a broad range of affinities by selecting how many of these interaction clusters will contribute to the overall binding free energy. Although the binding affinities of IL-4 and IL-13 to IL-4Rα differ by a factor of more than 1000, the specificity remains high because the receptor subunit IL-4Rα binds exclusively to IL-4 and IL-13. high specificity requires high affinity and vice versa. So far, affinity and specificity are often considered to co-vary, i.e. The modular architecture of the IL-4-IL-4Rα interface suggests a possible mechanism by which proteins might be able to generate binding affinity and specificity independently. Glu11 (cluster 1) and Arg64 (cluster 2), suggesting that IL-13 also uses this modular protein interface architecture. Mutagenesis studies reveal that IL-13 utilizes the same main binding determinants, i.e. All three clusters are fully engaged in these variants, generating a three-fold higher binding affinity for IL-4Rα. ![]() Mutating residues Thr13 or Phe82 located in cluster 3 to aspartate results in super-agonistic IL-4 variants. cluster 1 centered around Glu9 and cluster 2 around Arg88) contribute significantly to the free binding energy. For high-affinity binding of wild-type IL-4 to its receptor IL-4Rα, only two of these clusters ( i.e. Structural determination of a number of IL-4 variants together with in vitro binding studies show that IL-4 and its high-affinity receptor subunit IL-4Rα interact via a modular protein-protein interface consisting of three independently-acting interaction clusters. We present a structure/function analysis of the IL-4 ligand-receptor interaction. Knowledge of the binding mechanism will be important for the generation of either IL-4 or IL-13 specific drugs. IL-4 and IL-13 are interesting targets for allergy and asthma therapies. Since both cytokine ligands share only moderate similarity on the amino acid sequence level, molecular recognition of the ligands by both receptor subunits is of great interest. For signal transduction, both cytokines can utilise the same receptor, consisting of the IL-4Rα and the IL-13Rα1 chain, offering an explanation for their overlapping biological functions. Together with interleukin 13 (IL-13), IL-4 plays an important role in exacerbating allergic and asthmatic symptoms. Interleukin 4 (IL-4) is a key regulator of the immune system and an important factor in the development of allergic hypersensitivity. ![]()
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