Nucleoside diphosphate kinase A (NME1) catalyses its own oligophosphorylation

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Paper Summary

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Protein Makes Its Own Phosphate Chain: NME1's Auto-Oligophosphorylation Surprise

Researchers discovered that nucleoside diphosphate kinase A (NME1) can catalyze its own oligophosphorylation, a novel protein modification involving the addition of multiple phosphate groups to a single site (Thr94). This process depends on an initial phosphorylation and the catalytic activity of NME1 itself. Oligophosphorylation was observed in HEK293T cell lysates and appears to influence NME1's protein interactions.

Possible Conflicts of Interest

None identified

Identified Weaknesses

Limited scope of cell lines and models investigated

While the study demonstrated oligophosphorylation in vitro and in HEK293T cells, it's unclear how prevalent and relevant this modification is across different human cell types and tissues. Further investigation with diverse cell lines and models is needed to establish broader significance.

Lack of diverse structural characterization methods

The study primarily relies on MS and cryo-EM for structural characterization, without direct biochemical validation of the oligophosphorylation process. Confirmation using alternative methods like NMR or X-ray crystallography could strengthen the findings.

Functional consequences of protein interactions not explored

Although the study identified potential interactors of oligophosphorylated NME1, the functional consequences of these interactions are not fully explored. Additional experiments are needed to understand the downstream effects of oligophosphorylation on cellular processes.

Use of phosphoserine as a surrogate for phosphothreonine

The study uses phosphoserine (pS) as a surrogate for phosphothreonine (pT) in some experiments. While justified by higher protein yield, the impact of this substitution on the oligophosphorylation process and NME1 function needs further clarification.

Limited understanding of the functional significance

The functional significance of oligophosphorylation remains largely speculative. Further research is required to elucidate its precise role in cellular signaling and its potential impact on diseases like cancer.

Rating Explanation

This study presents a novel post-translational modification and provides strong evidence for its occurrence. The combination of chemical biology, mass spectrometry, and structural analysis is commendable. While some limitations exist (e.g., reliance on a single cell line for endogenous studies), the findings are significant and warrant further investigation.

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