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Tyrosine kinase signaling is tightly controlled by negative feedback inhibitors including suppressors of cytokine signaling (SOCS). SOCS assemble as SH2 domain substrate recognition modules in ElonginB/C-cullin ubiquitin ligases. In accordance, SOCS4 reduces STAT3 signaling from EGFR through increased receptor degradation. Variable C-termini in SOCS4-SOCS7 exclude these family members from a SOCS2-type domain arrangement in which a strictly conserved C terminus determines domain packing. The structure of the SOCS4-ElonginC-ElonginB complex reveals a distinct SOCS structural class. The N-terminal ESS helix functionally replaces the CIS/SOCS1-SOCS3 family C terminus in a distinct SH2-SOCS box interface that facilitates further interdomain packing between the extended N- and C-terminal regions characteristic for this subfamily. Using peptide arrays and calorimetry the STAT3 site in EGFR (pY(1092)) was identified as a high affinity SOCS4 substrate (K(D) = 0.5 microM) revealing a mechanism for EGFR degradation. SOCS4 also bound JAK2 and KIT with low micromolar affinity, whereas SOCS2 was specific for GH-receptor.

Original publication

DOI

10.1016/j.str.2007.09.016

Type

Journal article

Journal

Structure

Publication Date

11/2007

Volume

15

Pages

1493 - 1504

Keywords

Amino Acid Sequence, Binding Sites, Crystallography, X-Ray, Elongin, ErbB Receptors, Humans, Isoleucine, Models, Molecular, Molecular Sequence Data, Phosphotyrosine, STAT3 Transcription Factor, Sequence Alignment, Suppressor of Cytokine Signaling Proteins, Transcription Factors