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Structural insights into substrate recognition by the SOCS2 E3 ubiquitin ligase

DOI: 10.1038/s41467-019-10190-4 DOI Help

Authors: Wei-wei Kung (University of Dundee) , Sarath Ramachandran (University of Dundee) , Nikolai Makukhin (University of Dundee) , Elvira Bruno (University of Dundee) , Alessio Ciulli (University of Dundee)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 10 , PAGES 2534

State: Published (Approved)
Published: June 2019
Diamond Proposal Number(s): 14980

Open Access Open Access

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. Here, we report co-crystal 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 Å and 2.69 Å, respectively. Both peptides bind in an extended conformation recapitulating the canonical SH2 domain-pY pose, but capture different conformations of the EF loop via specific hydrophobic interactions. The flexible BG loop is fully defined in the electron density, and does not contact the substrate degron 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.

Journal Keywords: Biochemistry; Peptides; Proteins; Structural biology; X-ray crystallography

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography