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Structural insights into substrate recognition by the SOCS2 E3 ubiquitin ligase

Author

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  • 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)

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.

Suggested Citation

  • Wei-Wei Kung & Sarath Ramachandran & Nikolai Makukhin & Elvira Bruno & Alessio Ciulli, 2019. "Structural insights into substrate recognition by the SOCS2 E3 ubiquitin ligase," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10190-4
    DOI: 10.1038/s41467-019-10190-4
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    Cited by:

    1. Sarath Ramachandran & Nikolai Makukhin & Kevin Haubrich & Manjula Nagala & Beth Forrester & Dylan M. Lynch & Ryan Casement & Andrea Testa & Elvira Bruno & Rosaria Gitto & Alessio Ciulli, 2023. "Structure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Edmond M. Linossi & Kunlun Li & Gianluca Veggiani & Cyrus Tan & Farhad Dehkhoda & Colin Hockings & Dale J. Calleja & Narelle Keating & Rebecca Feltham & Andrew J. Brooks & Shawn S. Li & Sachdev S. Sid, 2021. "Discovery of an exosite on the SOCS2-SH2 domain that enhances SH2 binding to phosphorylated ligands," Nature Communications, Nature, vol. 12(1), pages 1-13, December.

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