A three-dimensional model of Suppressor Of Cytokine Signalling 1 (SOCS-1).
Suppressor Of Cytokine Signalling 1 (SOCS-1) is one of the proteins responsible for the negative regulation of the JAK-STAT pathway triggered by many cytokines. This important inhibition involves complex formation between SOCS-1 and JAK2, which requires particular structural domains (KIR, ESS and SH2) on SOCS-1. A three-dimensional theoretical model of SOCS-1 is presented here. The model was generated by the application of different modelling techniques, including threading, structure-based modelling, surface analysis and protein docking. The structure accounts for the interactions between SOCS-1 and two other key proteins in the JAK-STAT pathway, namely JAK2 and Elongin BC. The proposed model for the interaction between SOCS-1 and JAK2 suggests that the SOCS-1 suppress the kinase activity of JAK2 by obstructing the catalytic groove of the tyrosine kinase. Subsequent interaction of the JAK-SOCS complex with Elongin BC was also modelled. A sequence and structural comparison between the SH2 domain of SOCS-1 and the SH2 domains of other proteins highlights key residues that could be responsible for SOCS-1 specificity. Currently available mutational data are evaluated. The results are consistent with the experimental data and they provide deeper insights into the inhibitory function of SOCS-1 at a molecular level.
Giordanetto
Fabrizio
F
Department of Chemistry, Queen Mary, University of London, Mile End Road, London E1 4NS, UK.
Kroemer
Romano T
RT
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000075065:Elongin; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism; D018909:src Homology Domains
D000596:Amino Acids; D002352:Carrier Proteins; D000075065:Elongin; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2