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 SH...

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Bibliographic Details
Published in:Protein engineering 2003-02, Vol.16 (2), p.115-124
Main Authors: Giordanetto, Fabrizio, Kroemer, Romano T.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amino Acids - genetics
Amino Acids - metabolism
Carrier Proteins - chemistry
Carrier Proteins - genetics
Carrier Proteins - metabolism
Elongin
homology modelling
Intracellular Signaling Peptides and Proteins
JAK-STAT pathway
Janus Kinase 2
Models, Molecular
Molecular Sequence Data
Protein Conformation
Protein-Tyrosine Kinases - antagonists & inhibitors
Protein-Tyrosine Kinases - chemistry
Protein-Tyrosine Kinases - metabolism
Proto-Oncogene Proteins
Repressor Proteins - chemistry
Repressor Proteins - metabolism
Sequence Alignment
Sequence Homology, Amino Acid
Signal Transduction
SOCS
src Homology Domains
Structure-Activity Relationship
Substrate Specificity
Suppressor of Cytokine Signaling 1 Protein
Suppressor of Cytokine Signaling Proteins
Transcription Factors - chemistry
Transcription Factors - metabolism
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Summary: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.
ISSN:0269-2139
1741-0126
1460-213X
1741-0134
DOI:10.1093/proeng/gzg015