Structural insights into substrate recognition by the SOCS2 E3 ubiquitin ligase

Abstract

The suppressor of cytokine signaling 2 (SOCS2) acts as substrate recognition subunit of a Cullin5 E3 ubiquitin ligase complex. SOCS2 binds to phosphotyrosine-modified epitopes as degrons for ubiquitination and proteasomal degradation, yet the molecular basis of substrate recognition has remained elusive. We solved cocrystal structures of SOCS2-ElonginB-ElonginC in complex with phosphorylated peptides from substrates growth hormone receptor (GHR-pY595) and erythropoietin receptor (EpoR-pY426) at 1.98 A{square} and 2.69 A{square}, respectively. Both peptides bind in an extended conformation recapitulating the canonical SH2 domain-pY pose, yet capture different conformations of the EF loop via specific hydrophobic interactions. The flexible BG loop, for the first time fully defined in the electron density, does not contact the substrate degrons directly. Cancer-associated SNPs located around the pY pocket weaken substrate-binding affinity in biophysical assays. Our findings reveal insights into substrate recognition and specificity by SOCS2, and provide a blueprint for small molecule ligand design.