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Structure of the SOCS4-ElonginB/C complex reveals a distinct SOCS box interface and the molecular basis for SOCS-dependent EGFR degradation.

Authors
  • Bullock, Alex N
  • Rodriguez, Maria C
  • Debreczeni, Judit E
  • Songyang, Zhou
  • Knapp, Stefan
Type
Published Article
Journal
Structure (London, England : 1993)
Publication Date
Nov 01, 2007
Volume
15
Issue
11
Pages
1493–1504
Identifiers
PMID: 17997974
Source
Medline
License
Unknown

Abstract

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.

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