Structural Basis for Phosphotyrosine Recognition by Suppressor of Cytokine Signaling-3
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Suppressor of cytokine signaling (SOCS) proteins are indispensable negative regulators of cytokine-stimulated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathways. SOCS proteins (SOCS1-7 and CIS) consist of a variable N-terminal region, a central Src homology-2 (SH2) domain, and a C-terminal SOCS box. The N-terminal region in SOCS1 and SOCS3 includes the so-called kinase inhibitory region that has been shown to inhibit the catalytic activity of JAK2. Here, we present a crystal structure at 2.0 A resolution of the N-terminally extended SH2 domain of SOCS3 in complex with its phosphopeptide target on the cytokine receptor gp130. The structure reveals that major insertions in the EF and BG loops of the SOCS3 SH2 domain are responsible for binding to gp130 with high affinity and specificity. In addition, the structure provides insights into the possible mechanisms by which SOCS3 and SOCS1 inhibit JAK2 kinase activity.
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Available peptide co-structures for SOCS3 show an expanded hydrophobic pocket that may be more amenable to targeting.
“the available peptide co-structures for SOCS3 (refs 107,108,109 ) show an expanded hydrophobic pocket that may be more amenable to targeting”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [107]
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Targeted protein degradation: expanding the toolbox
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- Authors
- Bergamin, E., Wu, J., & Hubbard, S. R.
- Affiliations
- New York University (US)
- Corresponding author
- Hubbard, Stevan R.
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2006-08
- Volume
- 14
- Issue
- 8
- Pages
- 1285-1292
- ISSN
- 0969-2126 (ISSN-L)
- OpenAlex
- W2003140865
- Cited by
- 60
- References
- 39
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 2 · 2019: 2 · 2018: 1 · 2017: 2 · 2016: 4 · 2015: 1 · 2014: 5 · 2013: 4 · 2012: 3
- FWCI
- 2.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Structure (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK052916, DK052916)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- SOCS3, phosphotyrosine recognition, SH2 domain, gp130, JAK/STAT signaling, JAK2 inhibition, SOCS1, cytokine receptors, crystal structure
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Amino Acid Sequence, Crystallization, Models, Molecular, Molecular Sequence Data, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Signal Transduction, Sequence Alignment, Crystallography, X-Ray, Phosphotyrosine, Cytokine Receptor gp130, Suppressor of Cytokine Signaling Proteins, Janus Kinase 2
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