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Discovery of an exosite on the SOCS2-SH2 domain that enhances SH2 binding to phosphorylated ligands

Author

Listed:
  • Edmond M. Linossi

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Kunlun Li

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Gianluca Veggiani

    (The Donnelly Center for Cellular and Biomolecular Research, University of Toronto)

  • Cyrus Tan

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Farhad Dehkhoda

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Colin Hockings

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Dale J. Calleja

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Narelle Keating

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Rebecca Feltham

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Andrew J. Brooks

    (The University of Queensland Diamantina Institute)

  • Shawn S. Li

    (Schulich School of Medicine and Dentistry, University of Western Ontario)

  • Sachdev S. Sidhu

    (The Donnelly Center for Cellular and Biomolecular Research, University of Toronto)

  • Jeffrey J. Babon

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Nadia J. Kershaw

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Sandra E. Nicholson

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

Abstract

Suppressor of cytokine signaling (SOCS)2 protein is a key negative regulator of the growth hormone (GH) and Janus kinase (JAK)-Signal Transducers and Activators of Transcription (STAT) signaling cascade. The central SOCS2-Src homology 2 (SH2) domain is characteristic of the SOCS family proteins and is an important module that facilitates recognition of targets bearing phosphorylated tyrosine (pTyr) residues. Here we identify an exosite on the SOCS2-SH2 domain which, when bound to a non-phosphorylated peptide (F3), enhances SH2 affinity for canonical phosphorylated ligands. Solution of the SOCS2/F3 crystal structure reveals F3 as an α-helix which binds on the opposite side of the SH2 domain to the phosphopeptide binding site. F3:exosite binding appears to stabilise the SOCS2-SH2 domain, resulting in slower dissociation of phosphorylated ligands and consequently, enhances binding affinity. This biophysical enhancement of SH2:pTyr binding affinity translates to increase SOCS2 inhibition of GH signaling.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26983-5
    DOI: 10.1038/s41467-021-26983-5
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    References listed on IDEAS

    as
    1. Donald Metcalf & Christopher J. Greenhalgh & Elizabeth Viney & Tracy A. Willson & Robyn Starr & Nicos A. Nicola & Douglas J. Hilton & Warren S. Alexander, 2000. "Gigantism in mice lacking suppressor of cytokine signalling-2," Nature, Nature, vol. 405(6790), pages 1069-1073, June.
    2. 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.
    3. Robyn Starr & Tracy A. Willson & Elizabeth M. Viney & Leecia J. L. Murray & John R. Rayner & Brendan J. Jenkins & Thomas J. Gonda & Warren S. Alexander & Donald Metcalf & Nicos A. Nicola & Douglas J. , 1997. "A family of cytokine-inducible inhibitors of signalling," Nature, Nature, vol. 387(6636), pages 917-921, June.
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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. Fang-Ling Zhang & Zhen Hu & Yi-Fan Wang & Wen-Juan Zhang & Bo-Wei Zhou & Qi-Shun Sun & Ze-Bin Lin & Ke-Xuan Liu, 2023. "Organoids transplantation attenuates intestinal ischemia/reperfusion injury in mice through L-Malic acid-mediated M2 macrophage polarization," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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    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.

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