Related Experiment Video
Updated: Aug 14, 2025
12:47
Nuclear Magnetic Resonance Spectroscopy for the Identification of Multiple Phosphorylations of Intrinsically Disordered Proteins
Published on: December 27, 2016
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Comparative Protein Structural Network Analysis Reveals C-Terminal Tail Phosphorylation Structural Communication
Iris N Smith1, Jennifer E Dawson1, Charis Eng1,2,3,4,5
1Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, Ohio44195, United States.
The Journal of Physical Chemistry. B
|January 10, 2023
Summary
Phosphatase and tensin homolog (PTEN) CTT phosphorylation impacts its tumor suppressor function. This study reveals distinct conformational dynamics in PTEN-ASD versus PTEN-cancer mutations, identifying potential therapeutic targets.
Area of Science:
- Molecular Biology
- Biophysics
- Genetics
Background:
- PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a critical regulator of the PI3K/AKT/mTOR pathway.
- PTEN phosphorylation at its carboxy-terminal tail (CTT) inhibits its tumor suppressor activity by inducing an inactive conformation.
- Germline PTEN mutations cause PTEN hamartoma tumor syndrome (PHTS), linked to cancer and autism spectrum disorder (ASD).
Purpose of the Study:
- To investigate PTEN CTT phosphorylation-induced conformational dynamics in PTEN-ASD versus PTEN-cancer phenotypes.
- To elucidate the mechanistic details governing these dynamics in PHTS-associated mutations.
Main Methods:
- Comparative protein structure network (PSN)-based analysis.
- Investigated structural flexibility, inter-residue contacts, and allosteric communication patterns.
Main Results:
- Identified distinct patterns of structural flexibility, inter-residue contacts, and allosteric communication mediated by CTT phosphorylation between PTEN-ASD and PTEN-cancer phenotypes.
- Detected perturbations in global metapaths and community network connections within the active site and inter-domain regions.
- These findings highlight the role of these regions in transmitting information across the PTEN protein structure.
Conclusions:
- PTEN CTT phosphorylation dynamics provide a mechanistic basis for allosteric regulation in PTEN-ASD and PTEN-cancer mutations.
- Detailed analysis of PTEN variants reveals potential allosteric druggable targets for PHTS-associated conditions.
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