Structure of the SOCS4-ElonginB/C complex reveals a distinct SOCS box interface and the molecular basis for SOCS-dependent EGFR degradation.
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.
Bullock
Alex N
AN
University of Oxford, Structural Genomics Consortium, Botnar Research Centre, Oxford OX3 7LD, United Kingdom. alex.bullock@sgc.ox.ac.uk
Rodriguez
Maria C
MC
Debreczeni
Judit E
JE
Songyang
Zhou
Z
Knapp
Stefan
S
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D000075065:Elongin; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D007532:Isoleucine / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019000:Phosphotyrosine / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D016415:Sequence Alignment; D050826:Suppressor of Cytokine Signaling Proteins / Q000737:chemistry* / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism
D000075065:Elongin; C473084:SOCS4 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D007532:Isoleucine; D019000:Phosphotyrosine; C512478:EGFR protein, human; D066246:ErbB Receptors