From back to lower vertebrates. This conserved region is

From discussing the most noted potential roles of SOCS4, and SOCS5 it is apparent that they have similar roles in aiding viral clearance during influenza infection, and also in the negative regulation of EGFR signal transduction.  The SH2 domain, and SOCS box have been quite notably well characterized by extensive research into the overall structure of the SOCS proteins. However, there has been poor characterisation of the long N-terminal domain of the SOCS4-7 proteins, with many question marks remaining around the overall structure, and function it serves. The role of SOCS4, and SOCS5 in EGFR signalling was discussed in the previous section, and in that study, like in many other structural studies of SOCS, the N-terminal domain is removed as a precaution to prevent any unwanted effect on protein expression. Thus, the N terminal domain remains largely unanswered for, despite representing such a large protein proportion in SOCS4-7. The N-terminal domains of SOCS proteins are conserved across mammalian organisms, which tells us that the domain must play an important role in the regulation of cytokine signalling. A conserved region in the SOCS4, and SOCS5 N-terminal domain has been observed, and can be traced back to lower vertebrates. This conserved region is considered to be mostly disordered, and intrinsically disordered regions of proteins have been hypothesised to have specific functions in protein-protein interactions. These protein-protein interactions are predicted to occur in ways which are different to the modes of interaction utilised by their folded counterparts 42. The study has provided evidence that supports the prediction of a disordered N-terminal in SOCS. The N-terminal region has been found to be brimming with amino acids with higher flexible helices, as well as showing a depletion of hydrophobic amino acids. The properties associated with a disordered region such as that of the N-terminal of SOCS may contribute to their regulatory roles. A disordered region presents a large interaction surface, which also enables increased association, and dissociation rates, which are both of obvious benefit to the SOCS binding activities.  Although, the N-terminal region is described as being disordered, they suggest that short ordered regions exist within the long N-termini of SOCS 43. These ordered regions have been predicted in SOCS4, and 5, and are believed to contain a structured region made up of around 15-20 residues. The data published suggests that these regions represent molecular recognition motifs which play a role in scaffolding, and PPI (proton-pump inhibitors) functions. Following this research, progress was made in identifying the role of the conserved region on the SOCS5 disordered N-terminus. It has been proposed that the conserved region is a JAK interaction region (JIR). This conserved region is believed to mediate direct interaction with the JAK kinase domain. The drosophila type of SOCS5, SOC36E has been shown to regulate the JAK-STAT pathway through interactions mediated by the N-terminus which were independent of the SOCS box 44. As a result of high conservation, this discovery could mean that SOCS5 potentially plays a similar role in mice, and even humans. NMR chemical shift analysis, NOE analysis, and relaxation measurements were utilised to aid characterisation of the JIR, leading to new insights into the region. The results produced show that the JIR consists of an alpha helix which surrounds nine amino acid residues (224-233 on the N-terminus). The study has suggested that the performed alpha helix of the JIR on the N-terminus of SOCS5 plays a structural role, whilst also facilitating direct interaction to the JAK kinase domain 45. The same study postulated that SOCS4, along with the other SOCS which contain a largely disordered N-terminus, may also function in facilitating similar modes of function.

 From discussing the most noted potential roles of SOCS4, and SOCS5 it is apparent that they have similar roles in aiding viral clearance during influenza infection, and also in the negative regulation of EGFR signal transduction.  The SH2 domain, and SOCS box have been quite notably well characterized by extensive research into the overall structure of the SOCS proteins. However, there has been poor characterisation of the long N-terminal domain of the SOCS4-7 proteins, with many question marks remaining around the overall structure, and function it serves. The role of SOCS4, and SOCS5 in EGFR signalling was discussed in the previous section, and in that study, like in many other structural studies of SOCS, the N-terminal domain is removed as a precaution to prevent any unwanted effect on protein expression. Thus, the N terminal domain remains largely unanswered for, despite representing such a large protein proportion in SOCS4-7. The N-terminal domains of SOCS proteins are conserved across mammalian organisms, which tells us that the domain must play an important role in the regulation of cytokine signalling. A conserved region in the SOCS4, and SOCS5 N-terminal domain has been observed, and can be traced back to lower vertebrates. This conserved region is considered to be mostly disordered, and intrinsically disordered regions of proteins have been hypothesised to have specific functions in protein-protein interactions. These protein-protein interactions are predicted to occur in ways which are different to the modes of interaction utilised by their folded counterparts 42. The study has provided evidence that supports the prediction of a disordered N-terminal in SOCS. The N-terminal region has been found to be brimming with amino acids with higher flexible helices, as well as showing a depletion of hydrophobic amino acids. The properties associated with a disordered region such as that of the N-terminal of SOCS may contribute to their regulatory roles. A disordered region presents a large interaction surface, which also enables increased association, and dissociation rates, which are both of obvious benefit to the SOCS binding activities.  Although, the N-terminal region is described as being disordered, they suggest that short ordered regions exist within the long N-termini of SOCS 43. These ordered regions have been predicted in SOCS4, and 5, and are believed to contain a structured region made up of around 15-20 residues. The data published suggests that these regions represent molecular recognition motifs which play a role in scaffolding, and PPI (proton-pump inhibitors) functions. Following this research, progress was made in identifying the role of the conserved region on the SOCS5 disordered N-terminus. It has been proposed that the conserved region is a JAK interaction region (JIR). This conserved region is believed to mediate direct interaction with the JAK kinase domain. The drosophila type of SOCS5, SOC36E has been shown to regulate the JAK-STAT pathway through interactions mediated by the N-terminus which were independent of the SOCS box 44. As a result of high conservation, this discovery could mean that SOCS5 potentially plays a similar role in mice, and even humans. NMR chemical shift analysis, NOE analysis, and relaxation measurements were utilised to aid characterisation of the JIR, leading to new insights into the region. The results produced show that the JIR consists of an alpha helix which surrounds nine amino acid residues (224-233 on the N-terminus). The study has suggested that the performed alpha helix of the JIR on the N-terminus of SOCS5 plays a structural role, whilst also facilitating direct interaction to the JAK kinase domain 45. The same study postulated that SOCS4, along with the other SOCS which contain a largely disordered N-terminus, may also function in facilitating similar modes of function.

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