Discovery of an exosite on the SOCS2-SH2 domain that enhances SH2 binding to phosphorylated ligands
Details
Publication Year 2021-12-02, Volume 12, Issue #1, Page 7032
Journal Title
Nature Communications
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.
Publisher
NPG
WEHI Research Division(s)
Inflammation; Ubiquitin Signalling; Structural Biology
PubMed ID
34857742
Open Access at Publisher's Site
https://doi.org/10.1038/s41467-021-26983-5
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2021-12-07 12:04:07
Last Modified: 2021-12-07 01:32:18
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