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A new high affinity binding site for suppressor of cytokine signaling-3 on the erythropoietin receptor.
Hortner, Michael; Nielsch, Ulrich; Mayr, Lorenz M. et al.
2002In European Journal of Biochemistry, 269 (10), p. 2516-26
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Keywords :
Amino Acid Sequence; Animals; Binding Sites; Biosensing Techniques; COS Cells; Cell Line; Cloning, Molecular; Escherichia coli; Humans; Models, Molecular; Molecular Sequence Data; Mutagenesis; Phosphorylation; Protein Conformation; Proteins/chemistry/metabolism; Receptors, Erythropoietin/chemistry/metabolism; Repressor Proteins; Sequence Alignment; Suppressor of Cytokine Signaling Proteins; Transcription Factors; Tyrosine/metabolism; src Homology Domains
Abstract :
[en] Erythropoietin (Epo) is a hematopoietic cytokine that is crucial for the differentiation and proliferation of erythroid progenitor cells. Epo acts on its target cells by inducing homodimerization of the erythropoietin receptor (EpoR), thereby triggering intracellular signaling cascades. The EpoR encompasses eight tyrosine motifs on its cytoplasmic tail that have been shown to recruit a number of regulatory proteins. Recently, the feedback inhibitor suppressor of cytokine signaling-3 (SOCS-3), also referred to as cytokine-inducible SH2-containing protein 3 (CIS-3), has been shown to act on Epo signaling by both binding to the EpoR and the EpoR-associated Janus kinase 2 (Jak2) [Sasaki, A., Yasukawa, H., Shouda, T., Kitamura, T., Dikic, I. & Yoshimura, A. (2000) J. Biol. Chem 275, 29338-29347]. In this study tyrosine 401 was identified as a binding site for SOCS-3 on the EpoR. Here we show that human SOCS-3 binds to pY401 with a Kd of 9.5 microm while another EpoR tyrosine motif, pY429pY431, can also interact with SOCS-3 but with a ninefold higher affinity than we found for the previously reported motif pY401. In addition, SOCS-3 binds the double phosphorylated motif pY429pY431 more potently than the respective singly phosphorylated tyrosines indicating a synergistic effect of these two tyrosine residues with respect to SOCS-3 binding. Surface plasmon resonance analysis, together with peptide precipitation assays and model structures of the SH2 domain of SOCS-3 complexed with EpoR peptides, provide evidence for pY429pY431 being a new high affinity binding site for SOCS-3 on the EpoR.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Hortner, Michael
Nielsch, Ulrich
Mayr, Lorenz M.
Heinrich, Peter C.
Haan, Serge ;  Rheinisch - Westfälische Technische Hochschule Aachen - RWTH > Institute for Biochemistry
External co-authors :
yes
Language :
English
Title :
A new high affinity binding site for suppressor of cytokine signaling-3 on the erythropoietin receptor.
Publication date :
2002
Journal title :
European Journal of Biochemistry
ISSN :
1432-1033
Publisher :
Blackwell, Oxford, United Kingdom
Volume :
269
Issue :
10
Pages :
2516-26
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBilu :
since 26 April 2013

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