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- Title
Discovery of an exosite on the SOCS2-SH2 domain that enhances SH2 binding to phosphorylated ligands.
- Authors
Linossi, Edmond M.; Li, Kunlun; Veggiani, Gianluca; Tan, Cyrus; Dehkhoda, Farhad; Hockings, Colin; Calleja, Dale J.; Keating, Narelle; Feltham, Rebecca; Brooks, Andrew J.; Li, Shawn S.; Sidhu, Sachdev S.; Babon, Jeffrey J.; Kershaw, Nadia J.; Nicholson, Sandra E.
- 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. SOCS2 is a key regulator of growth hormone and cytokine signaling, which recognizes phosphotyrosine (pTyr)-modified targets via a central SH2 domain. Here, the authors discover and characterize an exosite on this SH2 domain that can bind a non-phosphorylated peptide to enhance SOCS2:pTyr affinity.
- Subjects
SOMATOTROPIN; SUPPRESSORS of cytokine signaling; LIGANDS (Biochemistry); BINDING sites; GROWTH regulators; PHOSPHOTYROSINE
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-26983-5