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Covalently Linked Protein Regulators

Covalently Linked Protein Regulators

Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....

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Updated: Feb 21, 2026

Fractionation for Resolution of Soluble and Insoluble Huntingtin Species

Fractionation for Resolution of Soluble and Insoluble Huntingtin Species

Published on: February 27, 2018

Post-translational modifications clustering within proteolytic domains decrease mutant huntingtin toxicity.

Nicolas Arbez¹, Tamara Ratovitski², Elaine Roby²

¹From the Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, narbez1@jhmi.edu.

The Journal of Biological Chemistry

|October 4, 2017

Summary

This summary is machine-generated.

Altering specific phosphorylation and acetylation sites on the huntingtin (Htt) protein can block neuronal toxicity and mitochondrial dysfunction in Huntington

Keywords:

Huntington disease neurodegeneration neuron phosphorylation toxicity

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Area of Science:

Neuroscience
Molecular Biology
Genetics

Background:

Huntington's disease (HD) is a neurodegenerative disorder primarily caused by polyglutamine expansion in the huntingtin (Htt) protein.
Post-translational modifications (PTMs) significantly influence protein function and cellular pathways; their role in mutant Htt pathogenesis is critical.
Previous studies suggest that modifying PTMs on Htt fragments can alter its cellular localization and toxicity.

Purpose of the Study:

To systematically investigate the impact of altering individual phosphorylation and acetylation sites on full-length Htt.
To assess how these PTM alterations affect neuronal toxicity and mitochondrial viability in the context of Huntington's disease.
To identify specific PTMs that modulate mutant Htt's pathogenic effects.

Main Methods:

Site-directed mutagenesis was used to alter individual phosphorylation and acetylation sites in full-length Htt constructs.
Functional assays, including a nuclear condensation assay, were employed to measure cell toxicity.
Mitochondrial viability was assessed by measuring mitochondrial membrane potential and size in primary neurons.

Main Results:

Alterations in specific PTM sites on Htt significantly reduced neuronal toxicity.
Modifying certain PTMs prevented mitochondrial dysfunction, including loss of potential and swelling, caused by mutant Htt.
Key PTM sites, including previously known (Serine 116) and newly identified (Serine 2652) sites, were found to be critical modulators of Htt toxicity and are clustered in protease-sensitive domains.

Conclusions:

Specific PTMs on the huntingtin protein play a crucial role in modulating Huntington's disease pathogenesis.
Targeting these identified PTMs offers a potential therapeutic strategy for Huntington's disease.
This research deepens the understanding of the Htt PTM code and its implications for neurodegenerative disease.