Structure of the SOCS4-ElonginB/C Complex Reveals a Distinct SOCS Box Interface and the Molecular Basis for SOCS-Dependent EGFR Degradation

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• 作者：Alex N. Bullock ; Maria C. Rodriguez ; Judit É ; . Debreczeni ; Zhou Songyang ; Stefan Knapp
• 关键词：PROTEINS ; SIGNALING
• 刊名：Structure
• 出版年：2007
• 出版时间：13 November 2007
• 年：2007
• 卷：15
• 期：11
• 页码：1493-1504
• 全文大小：1923 K

文摘

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 (pY¹⁰⁹²) was identified as a high affinity SOCS4 substrate (K_D = 0.5 μM) revealing a mechanism for EGFR degradation. SOCS4 also bound JAK2 and KIT with low micromolar affinity, whereas SOCS2 was specific for GH-receptor.