SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition
| Autor: | Isabelle S Lucet, Nicos A. Nicola, Nicholas P. D. Liau, Leila N. Varghese, Artem Laktyushin, Nadia J. Kershaw, James M. Murphy, Jeffrey J. Babon, Eden L Whitlock |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Cell signaling Molecular Sequence Data Suppressor of Cytokine Signaling Proteins Biology Article 03 medical and health sciences 0302 clinical medicine Structural Biology Humans SOCS3 Amino Acid Sequence Molecular Biology 030304 developmental biology 0303 health sciences Janus kinase 2 Binding Sites Janus kinase 1 Sequence Homology Amino Acid digestive oral and skin physiology JAK-STAT signaling pathway Janus Kinase 2 Interleukin-13 receptor 3. Good health Cell biology Biochemistry Suppressor of Cytokine Signaling 3 Protein 030220 oncology & carcinogenesis biology.protein Cytokines Signal transduction Janus kinase Protein Binding Signal Transduction |
| Zdroj: | Nature structural & molecular biology |
| ISSN: | 1545-9985 |
| Popis: | The inhibitory protein SOCS3 plays a key part in the immune and hematopoietic systems by regulating signaling induced by specific cytokines. SOCS3 functions by inhibiting the catalytic activity of Janus kinases (JAKs) that initiate signaling within the cell. We determined the crystal structure of a ternary complex between mouse SOCS3, JAK2 (kinase domain) and a fragment of the interleukin-6 receptor β-chain. The structure shows that SOCS3 binds JAK2 and receptor simultaneously, using two opposing surfaces. While the phosphotyrosine-binding groove on the SOCS3 SH2 domain is occupied by receptor, JAK2 binds in a phosphoindependent manner to a noncanonical surface. The kinase-inhibitory region of SOCS3 occludes the substrate-binding groove on JAK2, and biochemical studies show that it blocks substrate association. These studies reveal that SOCS3 targets specific JAK-cytokine receptor pairs and explains the mechanism and specificity of SOCS action. |
| Databáze: | OpenAIRE |
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