From phosphoproteins to phosphoproteomes: a historical account

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Abstract

The first phosphoprotein (casein) was discovered in 1883, yet the enzyme responsible for its phosphorylation was identified only 130 years later, in 2012. In the intervening time, especially in the last decades of the 1900s, it became evident that, far from being an oddity, phosphorylation affects the majority of eukaryotic proteins during their lifespan, and that this reaction is catalysed by the members of a large family of protein kinases, susceptible to a variety of stimuli controlling nearly every aspect of life and death. The aim of this review is to present a historical account of the main steps of this spectacular revolution, which transformed our conception of a biochemical reaction originally held as a sporadic curiosity into the master mechanism governing cell regulation, and, if it is perturbed, causing cell dysregulation.

From the origin to the ‘omic’ era of protein phosphorylation: an enticing story made of pioneers, doubts and success in the discovery of one of the most significant post-translational modifications, governing almost all cellular events. This State-of-the-Art Review covers protein phosphorylation from the discovery of the first phosphoprotein in 1883 to our present-day knowledge of all phosphosites in the human proteome identified by mass spectrometry.

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