Impact of E334Q Mutation on Cytoskeletal Gamma-Actin

Core Concepts

The author explores the impact of the E334Q mutation in cytoskeletal gamma-actin on interactions with myosin and ADF/cofilin family proteins, shedding light on the underlying molecular mechanisms of non-muscle actinopathies.

Abstract

The content delves into the biochemical characterization of human cytoskeletal gamma-actin carrying the E334Q mutation, revealing its effects on actin filament dynamics, myosin motor interactions, and cofilin-mediated processes. The mutation does not compromise protein folding or stability but significantly impairs interactions with myosins and ADF/cofilins. These findings provide insights into the pathogenesis of non-muscle actinopathies associated with specific mutations in actin isoforms. Key points highlighted include: The E334Q mutation affects interactions with myosins and ADF/cofilins. Mutant filaments show reduced sliding velocity and altered cofilin-mediated dynamics. Structural analysis reveals changes in actomyosin interfaces due to the mutation. Biochemical assays demonstrate differences in nucleotide exchange rates and polymerization behavior. The study emphasizes the importance of understanding molecular mechanisms underlying actinopathies for disease diagnosis and treatment.

Stats

Following an initial lag phase of 200 to 300 seconds, mutant filaments showed faster de novo filament nucleation compared to wild-type. The observed rate constant values were linearly dependent on the concentration of cofilin–1 in the range 0–40 nM. Mutation E334Q leads to a weakening of complementary electrostatic interactions between actin and cofilins.

Quotes

"The mutant protein efficiently copolymerizes with wildtype monomers and integrates into linear and branched filament networks." "E334Q differentially affects cofilin-mediated actin dynamics by increasing de novo nucleation rates while decreasing filament severing efficiency."

Key Insights Distilled From

The non–muscle actinopathy–associated mutation E334Q in cytoskeletal γ– actin perturbs interaction of actin filaments with myosin and ADF/cofilin family proteins

by Greve,J. N.,... at www.biorxiv.org 09-10-2023

https://www.biorxiv.org/content/10.1101/2023.09.10.557040v3

Deeper Inquiries

How do mutations in actin isoforms contribute to various syndromes beyond non-muscle actinopathies

Mutations in actin isoforms can contribute to various syndromes beyond non-muscle actinopathies through different mechanisms. These mutations can lead to functional haploinsufficiency, where the mutated molecule is unstable or unable to interact with other actin molecules properly, resulting in a reduced amount of active actin. Additionally, mutations may interfere with actin filament turnover, perturb interactions with actin-binding proteins (ABPs), or increase the propensity for forming toxic oligomeric structures. These disruptions in normal cellular processes can result in a spectrum of rare syndromes that manifest as developmental disorders affecting multiple organs and systems.

What implications do changes in actomyosin interactions have for cellular processes like migration and mechanotransduction

Changes in actomyosin interactions have significant implications for essential cellular processes like migration and mechanotransduction. Actomyosin interactions are crucial for generating contractile forces necessary for cell movement and adhesion during migration. Perturbations in these interactions due to mutations can lead to impaired cell motility and altered responses to mechanical cues from the environment. This disruption affects directed migration, adhesion dynamics, division processes, and mechanotransduction pathways within cells.

How can insights from studying specific mutations in cytoskeletal gamma-actins be applied to develop targeted therapies for related disorders

Insights gained from studying specific mutations in cytoskeletal gamma-actins provide valuable information that can be applied towards developing targeted therapies for related disorders. By understanding how these mutations affect protein folding, stability, polymerization behavior, interaction with myosins and ABPs like cofilin-1 at a molecular level, researchers can identify potential therapeutic targets or strategies aimed at restoring normal function. Targeted interventions could include modulating protein-protein interactions involved in cytoskeletal dynamics or developing small molecules that specifically target mutant forms of cytoskeletal gamma-actins while preserving normal cellular functions.