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

Edmond M. Linossi, Kunlun Li, Gianluca Veggiani, Cyrus Tan, Farhad Dehkhoda, Colin Hockings, Dale J. Calleja, Narelle Keating, Rebecca Feltham, Andrew J. Brooks, Shawn S. Li, Sachdev S. Sidhu, Jeffrey J. Babon, Nadia J. Kershaw () and Sandra E. Nicholson ()
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Edmond M. Linossi: The Walter and Eliza Hall Institute of Medical Research
Kunlun Li: The Walter and Eliza Hall Institute of Medical Research
Gianluca Veggiani: The Donnelly Center for Cellular and Biomolecular Research, University of Toronto
Cyrus Tan: The Walter and Eliza Hall Institute of Medical Research
Farhad Dehkhoda: The Walter and Eliza Hall Institute of Medical Research
Colin Hockings: The Walter and Eliza Hall Institute of Medical Research
Dale J. Calleja: The Walter and Eliza Hall Institute of Medical Research
Narelle Keating: The Walter and Eliza Hall Institute of Medical Research
Rebecca Feltham: The Walter and Eliza Hall Institute of Medical Research
Andrew J. Brooks: The University of Queensland Diamantina Institute
Shawn S. Li: Schulich School of Medicine and Dentistry, University of Western Ontario
Sachdev S. Sidhu: The Donnelly Center for Cellular and Biomolecular Research, University of Toronto
Jeffrey J. Babon: The Walter and Eliza Hall Institute of Medical Research
Nadia J. Kershaw: The Walter and Eliza Hall Institute of Medical Research
Sandra E. Nicholson: The Walter and Eliza Hall Institute of Medical Research

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26983-5

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DOI: 10.1038/s41467-021-26983-5

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