Structural basis for phosphotyrosine recognition by suppressor of cytokine signaling-3.
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.
Bergamin
Elisa
E
Structural Biology Program, Skirball Institute of Biomolecular Medicine and Department of Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
Wu
Jinhua
J
Hubbard
Stevan R
SR
D000595:Amino Acid Sequence; D003460:Crystallization; D018360:Crystallography, X-Ray; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D053614:Janus Kinase 2; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019000:Phosphotyrosine / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction / Q000235:genetics*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D011518:Proto-Oncogene Proteins; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D050822:Cytokine Receptor gp130; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2