A back-door insight into the modulation of Src kinase activity by the polyamine spermidine
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eLife assessment
This is an important study describing the mechanism of Spermidine modulation of Src kinase, identifying the interacting amino acids and the effect on indoleamine 2,3-dioxygenase 1 (IDO1) activation based on solid evidence. Considering the important role of IDO1 in the immune response this study could provide important information for the design of allosteric modulators capable of turning SRC on/off.
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Abstract
Src is a protein tyrosine kinase commonly activated downstream of transmembrane receptors and plays key roles in cell growth, migration, and survival signaling pathways. In conventional dendritic cells (cDCs), Src is involved in the activation of the non-enzymatic functions of indoleamine 2,3-dioxygenase 1 (IDO1), an immunoregulatory molecule endowed with both catalytic activity and signal transducing properties. Prompted by the discovery that the metabolite spermidine confers a tolerogenic phenotype on cDCs that is dependent on both the expression of IDO1 and the activity of Src kinase, we here investigated the spermidine mode of action. We found that spermidine directly binds Src in a previously unknown allosteric site located on the backside of the SH2 domain and thus acts as a positive allosteric modulator of the enzyme. Besides confirming that Src phosphorylates IDO1, here we showed that spermidine promotes the protein–protein interaction of Src with IDO1. Overall, this study may pave the way toward the design of allosteric modulators able to switch on/off the Src-mediated pathways, including those involving the immunoregulatory protein IDO1.
Article activity feed
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eLife assessment
This is an important study describing the mechanism of Spermidine modulation of Src kinase, identifying the interacting amino acids and the effect on indoleamine 2,3-dioxygenase 1 (IDO1) activation based on solid evidence. Considering the important role of IDO1 in the immune response this study could provide important information for the design of allosteric modulators capable of turning SRC on/off.
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Reviewer #1 (Public Review):
The manuscript described the mechanism of Spermidine modulation of Src kinase on IDO1, accelerating the kinetics of the reaction. Spermidine can act on the backside of the SH2 domain of Src, by the interaction of specific amino acids. Considering the important role of IDO1 in the immune response the results provide proof of principle for the development of molecules that can modulate the kinase activity and the nonenzymatic functions of Src and IDO1 at once. The conclusions of this paper are mostly well supported by data, but some aspects of figure construction and data analysis need to be improved for the sake of clarity.
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Reviewer #2 (Public Review):
Src is a well-studied non-receptor protein tyrosine kinase (PTK) with broad impacts on many signal transduction pathways. In this manuscript titled, "A Back-Door Insights into the modulation of Src kinase activity by the polyamine spermidine" Rossini et al investigated the mechanism of spermidine, a natural polyamine, in regulating Src tyrosine kinase activity and complex formation with IDO1, a known Src substrate. These data show a direct binding, and an allosteric binding site in the SH2 domain of Src, for spermidine. Interestingly, the manuscript also shows spermidine bound to Src promotes binding to IDO1, as well as its phosphorylation.
Overall, the molecular glue-like property of spermidine is an interesting finding. That Src substrate binding and phosphorylation for Src substrate is regulated by …
Reviewer #2 (Public Review):
Src is a well-studied non-receptor protein tyrosine kinase (PTK) with broad impacts on many signal transduction pathways. In this manuscript titled, "A Back-Door Insights into the modulation of Src kinase activity by the polyamine spermidine" Rossini et al investigated the mechanism of spermidine, a natural polyamine, in regulating Src tyrosine kinase activity and complex formation with IDO1, a known Src substrate. These data show a direct binding, and an allosteric binding site in the SH2 domain of Src, for spermidine. Interestingly, the manuscript also shows spermidine bound to Src promotes binding to IDO1, as well as its phosphorylation.
Overall, the molecular glue-like property of spermidine is an interesting finding. That Src substrate binding and phosphorylation for Src substrate is regulated by natural metabolites like spermidine is also a new and interesting finding. These discoveries further strengthen the idea to develop potential allosteric modulators for Src/PTK-mediated pathways.
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Reviewer #3 (Public Review):
The manuscript by Rossini et al suggests an interesting novel mechanism for the regulation of tyrosine kinase Src by spermidine. The idea is interesting and some of the data suggest that spermidine may regulate Src activity. However, the manuscript suffers from multiple major shortcomings. The mechanism proposed by the authors is not supported by their studies. Authors tend to overinterpret data and overlook critical information that is missing. Some of the data is insufficient to support the statements that the authors make. Authors tend to use confusing nomenclature without clarifications making it difficult to interpret the data. The extent of Src activation by spermidine should be carefully evaluated by comparing it to the maximum activity of constitutively active Src. Furthermore, the biological …
Reviewer #3 (Public Review):
The manuscript by Rossini et al suggests an interesting novel mechanism for the regulation of tyrosine kinase Src by spermidine. The idea is interesting and some of the data suggest that spermidine may regulate Src activity. However, the manuscript suffers from multiple major shortcomings. The mechanism proposed by the authors is not supported by their studies. Authors tend to overinterpret data and overlook critical information that is missing. Some of the data is insufficient to support the statements that the authors make. Authors tend to use confusing nomenclature without clarifications making it difficult to interpret the data. The extent of Src activation by spermidine should be carefully evaluated by comparing it to the maximum activity of constitutively active Src. Furthermore, the biological significance of this regulation is not demonstrated. Only a few overexpression data are shown.
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