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

  • Nat Commun. 2021 Dec 2;12(1):7032. doi: 10.1038/s41467-021-26983-5.
Edmond M Linossi  #  1  2 ,  Kunlun Li  #  1  2 ,  Gianluca Veggiani  #  3 ,  Cyrus Tan  1  2 ,  Farhad Dehkhoda  1  2 ,  Colin Hockings  1  2 ,  Dale J Calleja  1  2 ,  Narelle Keating  1  2 ,  Rebecca Feltham  1  2 ,  Andrew J Brooks  4 ,  Shawn S Li  5 ,  Sachdev S Sidhu  3 ,  Jeffrey J Babon  1  2 ,  Nadia J Kershaw  6  7 ,  Sandra E Nicholson  8  9
Affiliations
  • 1. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
  • 2. Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
  • 3. The Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada.
  • 4. The University of Queensland Diamantina Institute, Woolloongabba, QLD, 4102, Australia.
  • 5. Department of Biochemistry and the Siebens-Drake Medical Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada.
  • 6. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. [email protected].
  • 7. Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia. [email protected].
  • 8. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. [email protected].
  • 9. Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia. [email protected].
  • # Contributed equally.
PMID: 34857742 DOI: 10.1038/s41467-021-26983-5
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.