Issue 10, 2015

The generation of phosphoserine stretches in phosphoproteins: mechanism and significance

Abstract

In the infancy of studies on protein phosphorylation the occurrence of clusters of three or more consecutive phosphoseryl residues in secreted and in cellular phosphoproteins was reported. Later however, while the reversible phosphorylation of Ser, Thr and Tyr residues was recognized to be the most frequent and general mechanism of cell regulation and signal transduction, the phenomenon of multi-phosphorylation of adjacent residues was entirely neglected. Nowadays, in the post-genomic era, the availability of large phosphoproteomics database makes possible a comprehensive re-visitation of this intriguing aspect of protein phosphorylation, aimed at shedding light on both its mechanistic occurrence and its functional meaning. Here we describe an analysis of the human phosphoproteome disclosing the existence of more than 800 rows of 3 to >10 consecutive phosphoamino acids, composed almost exclusively of phosphoserine, while clustered phosphothreonines and phosphotyrosines are almost absent. A scrutiny of these phosphorylated rows supports the conclusion that they are generated through the major contribution of a few hierarchical protein kinases, with special reference to CK2. Also well documented is the combined intervention of CK1 and GSK3, the former acting as priming and primed, the latter as primed kinase. The by far largest proportion of proteins containing (pS)n clusters display a nuclear localization where they play a prominent role in the regulation of transcription. Consistently the molecular function of the by far largest majority of these proteins is the ability to bind other macromolecules and/or nucleotides and metal ions. A “String” analysis performed under stringent conditions reveals that >80% of them are connected to each other by physical and/or functional links, and that this network of interactions mostly take place at the nuclear level.

Graphical abstract: The generation of phosphoserine stretches in phosphoproteins: mechanism and significance

Supplementary files

Article information

Article type
Review Article
Submitted
15 میٔ 2015
Accepted
16 جوٗلایی 2015
First published
17 جوٗلایی 2015

Mol. BioSyst., 2015,11, 2666-2679

Author version available

The generation of phosphoserine stretches in phosphoproteins: mechanism and significance

L. Cesaro and L. A. Pinna, Mol. BioSyst., 2015, 11, 2666 DOI: 10.1039/C5MB00337G

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