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Related Experiment Video

Updated: Jan 16, 2026

Oligopeptide Competition Assay for Phosphorylation Site Determination

Oligopeptide Competition Assay for Phosphorylation Site Determination

Published on: May 18, 2017

Mapping cryptic phosphorylation sites in the human proteome.

Dino Gasparotto^1,2, Annarita Zanon^1,3,4, Valerio Bonaldo¹

¹Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, Trento, 38121, Italy.

The EMBO Journal

|October 3, 2025

Summary

This summary is machine-generated.

Many proteins have hidden phosphorylation sites that become exposed during folding. This cryptic phosphorylation influences protein stability, degradation, and cancer development, revealing new roles in cell regulation.

Keywords:

Co-translational Phosphorylation Cryptic Phosphosites Post-translation Modification Protein Folding Protein Phosphorylation

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Last Updated: Jan 16, 2026

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Published on: May 18, 2017

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Published on: May 22, 2018

Area of Science:

Biochemistry
Molecular Biology
Proteomics

Background:

Transient protein folding intermediates are increasingly recognized for their biological roles.
Post-translational modifications (PTMs) can occur on residues exposed during protein folding.

Purpose of the Study:

To investigate if post-translational modifications, specifically phosphorylation, occur on residues exposed during protein folding.
To explore the functional and evolutionary implications of these modifications.

Main Methods:

Analysis of solvent accessibility for 87,138 post-translationally modified amino acids in the human proteome.
Computational and experimental validation of cryptic phosphosite exposure.
Phylogenetic analysis of phosphosite conservation.
Cross-referencing with cancer mutation databases.

Main Results:

One-third of phosphorylated proteins contain at least one phosphosite buried within the protein core.
These cryptic phosphosites may be exposed during folding, potentially destabilizing native structures and promoting degradation.
Cryptic phosphosites show higher conservation than surface-exposed ones.
Phosphomimetic mutations in cryptic sites can enhance tumor fitness by inactivating tumor suppressors.

Conclusions:

Cryptic phosphorylation plays a novel role in shaping protein folding and expression.
This mechanism has implications for protein regulation, degradation, and cancer.
Further research into cryptic phosphorylation in health and disease is warranted.