New mimetic peptides of the kinase-inhibitory region (KIR) of SOCS1 through focused peptide libraries(1334 views) Doti N, Scognamiglio PL, Madonna S, Scarponi C, Ruvo M, Perretta G, Albanesi C, Marasco D
Keywords: Janus Kinase Signal Transducer And Activator Of Transcription Pathway (jak Stat Pathway), Kinase Inhibitory Region (kir), Mimetic Peptide, Peptide Library, Suppressor Of Cytokine Signalling 1 (socs1), Gamma Interferon, Interferon Regulatory Factor 1, Stat1 Protein, Suppressor Of Cytokine Signaling 1, Amino Acid Sequence, Article, Binding Affinity, Catalysis, Controlled Study, Enzyme Activation, Enzyme Activity, Enzyme Stability, Human, Human Cell, Keratinocyte, Normal Human, Priority Journal, Protein Analysis, Protein Binding, Protein Function, Protein Interaction, Protein Phosphorylation, Protein Structure, Protein Synthesis, Signal Transduction, Competitive, Catalytic Domain, Cultured, Circular Dichroism, Drug Evaluation, Preclinical, Drug Stability, Models, Molecular, Molecular Sequence Data, Secondary, Tertiary, Stat1 Transcription Factor, Suppressor Of Cytokine Signaling Proteins,
Affiliations: *** IBB - CNR ***
Institute of Biostructures and Bioimaging - IBB-CNR, Via Mezzocannone 16, 80134, Naples, Italy
Laboratory of Experimental Immunology, Istituto Dermopatico dell'Immacolata, Via Monti di Creta 104, 00167 Rome, Italy
Department of Biological Sciences, School of Biotechnological Sciences, University Federico II, Via Mezzocannone 16, 80134, Naples, Italy
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Flowers, L. O., Johnson, H. M., Mujtaba, M. G., Ellis, M. R., Haider, S. M. I., Subramaniam, P. S., Characterization of a peptide inhibitor of Janus kinase 2 that mimics suppressor of cytokine signaling 1 function (2004) Journal of Immunology, 172 (12), pp. 7510-7518
Waiboci, L. W., Ahmed, C. M., Mujtaba, M. G., Flowers, L. O., Martin, J. P., Haider, M. I., Johnson, H. M., Both the suppressor of cytokine signaling 1 (SOCS-1) kinase inhibitory region and SOCS-1 mimetic bind to JAK2 autophosphorylation site: Implications for the development of a SOCS-1 antagonist (2007) Journal of Immunology, 178 (8), pp. 5058-5068
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Chang, C. -Y., Norris, J. D., Gron, H., Paige, L. A., Hamilton, P. T., Kenan, D. J., Fowlkes, D., McDonnell, D. P., Dissection of the LXXLL nuclear receptor-coactivator interaction motif using combinatorial peptide libraries: Discovery of peptide antagonists of estrogen receptors and (1999) Molecular and Cellular Biology, 19 (12), pp. 8226-8239
Northrop, J. P., Nguyen, D., Piplani, S., Olivan, S. E., Kwan, S. T. -S., Go, N. F., Hart, C. P., Schatz, P. J., Selection of estrogen receptor - and Thyroid hormone receptor -specific coactivator-mimetic peptides using recombinant peptide libraries (2000) Molecular Endocrinology, 14 (5), pp. 605-622. , DOI 10. 1210/me. 14. 5. 605
Burke, M. D., Berger, E. M., Schreiber, S. L., Generating Diverse Skeletons of Small Molecules Combinatorially (2003) Science, 302 (5645), pp. 613-618. , DOI 10. 1126/science. 1089946
Burke, M. D., Khan, S. A., Triggered enzymatic degradation of a water-soluble polymer solution using a novel inhibitor (2000) Biomacromolecules, 1, pp. 688-695
Geysen, H. M., Rodda, S. J., Mason, T. J., A priori delineation of a peptide which mimics a discontinuous antigenic determinant (1986) Molecular Immunology, 23 (7), pp. 709-715. , DOI 10. 1016/0161-5890 (86) 90081-7
Bos, J. D., De Korte, J., Effects of etanercept on quality of life, fatigue, and depression in psoriasis (2006) Lancet, 367 (9504), pp. 6-7. , DOI 10. 1016/S0140-6736 (05) 67818-X, PII S014067360567818X
Babon, J. J., Sabo, J. K., Zhang, J. G., Nicola, N. A., Norton, R. S., The SOCS box encodes a hierarchy of affinities for Cullin5: Implications for ubiquitin ligase formation and cytokine signalling suppression (2009) J. Mol. Biol., 387, pp. 162-174
New mimetic peptides of the kinase-inhibitory region (KIR) of SOCS1 through focused peptide libraries
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 SOCS I in keratinocyte clones abrogates the IFN gamma (interferon gamma)-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 K-d 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).
New mimetic peptides of the kinase-inhibitory region (KIR) of SOCS1 through focused peptide libraries
No results.
New mimetic peptides of the kinase-inhibitory region (KIR) of SOCS1 through focused peptide libraries