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Covalently Linked Protein Regulators

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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.
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Immunostaining for DNA Modifications: Computational Analysis of Confocal Images

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Methylation-regulated decommissioning of multimeric PP2A complexes.

Cheng-Guo Wu^1,2, Aiping Zheng^1,3, Li Jiang^1,4

¹McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin at Madison, School of Medicine and Public Health, Madison, WI, 53705, USA.

Nature Communications

|December 24, 2017

Summary

This summary is machine-generated.

The butterfly-shaped TIPRL protein inactivates protein phosphatase 2A (PP2A) by binding its catalytic subunit. TIPRL and chaperone α4 work together to disassemble active PP2A, a process controlled by methylation.

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Assays for the Degradation of Misfolded Proteins in Cells

Assays for the Degradation of Misfolded Proteins in Cells

Published on: August 28, 2016

Area of Science:

Cellular Biology
Molecular Biology
Biochemistry

Background:

Dynamic assembly and disassembly of protein complexes are essential for cellular signaling.
Protein Phosphatase 2A (PP2A) holoenzymes, composed of scaffold, catalytic, and regulatory subunits, are critical for cellular functions.
Specialized chaperones regulate the biogenesis of PP2A holoenzymes.

Purpose of the Study:

To elucidate the mechanism by which TIPRL (TOR signaling pathway regulator) interacts with and regulates PP2A holoenzymes.
To investigate the role of TIPRL in PP2A holoenzyme assembly, inactivation, and disassembly.
To understand how TIPRL and other chaperones, like α4, coordinate PP2A regulation in a methylation-dependent manner.

Main Methods:

Structural analysis of TIPRL-PP2A interactions.
Biochemical assays to assess PP2A activity and holoenzyme assembly.
Investigation of the effects of disease-associated PP2A mutations on TIPRL binding and PP2A function.
Studies on the interplay between TIPRL, α4, and PP2A methylation status.

Main Results:

TIPRL binds the PP2A catalytic subunit, targeting unmethylated forms and inhibiting phosphatase activity.
TIPRL interacts with the PP2A scaffold subunit, accommodating disease mutations that disrupt assembly and enhance inactivation.
TIPRL and the latency chaperone α4 cooperate to disassemble active PP2A holoenzymes into latent forms, regulated by methylation.
TIPRL's unique binding allows it to tolerate PP2A mutations that impede other regulatory subunits.

Conclusions:

TIPRL acts as a key regulator of PP2A, mediating methylation-responsive inactivation and holoenzyme disassembly.
The study reveals a novel mechanism for controlling PP2A activity through TIPRL and α4, highlighting the importance of methylation.
Understanding TIPRL-PP2A interactions provides insights into cellular signaling complexity and the pathogenesis of diseases linked to PP2A dysfunction, including cancer and intellectual disability.