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

Linossi, EM; Li, K; Veggiani, G; Tan, C; Dehkhoda, F; Hockings, C; Calleja, DJ; Keating, N; Feltham, R; Brooks, AJ; Li, SS; Sidhu, SS; Babon, JJ; Kershaw, NJ; Nicholson, SE

Author(s): Linossi, EM; Li, K; Veggiani, G; Tan, C; Dehkhoda, F; Hockings, C; Calleja, DJ; Keating, N; Feltham, R; Brooks, AJ; Li, SS; Sidhu, SS; Babon, JJ; Kershaw, NJ; Nicholson, SE;
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
Research Division(s): Inflammation; Ubiquitin Signalling; Structural Biology
PubMed ID: 34857742
Publisher's Version: https://doi.org/10.1038/s41467-021-26983-5
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-021-26983-5
Terms of Use/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