Biochemical journal, 2012-04, Vol.443 (1), p.231-240
2012
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Details
- Autor(en) / Beteiligte
- Titel
- New mimetic peptides of the kinase-inhibitory region (KIR) of SOCS1 through focused peptide libraries
- Ist Teil von
- Biochemical journal, 2012-04, Vol.443 (1), p.231-240
- Ort / Verlag
- England
- Erscheinungsjahr
- 2012
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- SOCS (suppressor of cytokine signalling) proteins are negative-feedback regulators of the JAK (Janus kinase)/STAT (signal transducer and activator of transcription) pathway. Their expression levels are low under physiological conditions, but they are up-regulated in response to cytokine stimulation in many immune and inflammatory processes. Overexpression of SOCS1 in keratinocyte clones abrogates the IFNγ (interferon γ)-induced expression of many pro-inflammatory genes and the release of related chemokines by blocking the JAK/STAT pathway. SOCS1 inhibits JAK2 kinase activity by binding the catalytic site of JAK2, with its KIR (kinase-inhibitory region) acting as a pseudo-substrate of the enzyme. In the present study, we screened a focused combinatorial peptide library of KIR to identify new peptides able to mimic its function with an improved affinity towards the JAK2 catalytic site. Using an alanine-scanning method, KIR residues that are crucial for the interaction with JAK2 were unveiled. In this way, the KIR sequence was restricted to a shorter segment and ‘non-essential’ residues were replaced by different amino acids following a simplified combinatorial approach. We selected a new unnatural sequence able to bind to JAK2 with Kd values in the nanomolar range. This peptide was tested in human keratinocyte cultures and reduced the phosphorylation of STAT1 and the expression levels of IRF-1 (interferon regulatory factor-1).
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0264-6021eISSN: 1470-8728DOI: 10.1042/BJ20111647Titel-ID: cdi_proquest_miscellaneous_1008846912
- Format
- –
- Schlagworte
- Amino Acid Sequence, Binding, Competitive, Catalytic Domain, Cells, Cultured, Circular Dichroism, Drug Evaluation, Preclinical, Drug Stability, Humans, Interferon Regulatory Factor-1 - genetics, Interferon Regulatory Factor-1 - metabolism, Janus Kinase 2 - antagonists & inhibitors, Janus Kinase 2 - chemistry, Janus Kinase 2 - metabolism, Keratinocytes - drug effects, Keratinocytes - metabolism, Models, Molecular, Molecular Sequence Data, Peptide Library, Peptides - chemistry, Peptides - metabolism, Peptides - pharmacology, Phosphorylation, Protein Binding, Protein Structure, Secondary, Protein Structure, Tertiary, STAT1 Transcription Factor - metabolism, Suppressor of Cytokine Signaling 1 Protein, Suppressor of Cytokine Signaling Proteins - chemistry