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

Authors

Edmond M. Linossi, Walter and Eliza Hall Institute of Medical Research
Kunlun Li, Walter and Eliza Hall Institute of Medical Research
Gianluca Veggiani, University of Toronto
Cyrus Tan, Walter and Eliza Hall Institute of Medical Research
Farhad Dehkhoda, Walter and Eliza Hall Institute of Medical Research
Colin Hockings, Walter and Eliza Hall Institute of Medical Research
Dale J. Calleja, Walter and Eliza Hall Institute of Medical Research
Narelle Keating, Walter and Eliza Hall Institute of Medical Research
Rebecca Siu, Hospital for Sick Children University of Toronto
Monika Wojtera, Schulich School of Medicine & Dentistry
Murad Husein, London Health Sciences CentreFollow

Document Type

Article

Publication Date

12-1-2021

Journal

Nature Communications

Volume

12

Issue

1

URL with Digital Object Identifier

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.