Related Experiment Video

Updated: Aug 1, 2025

Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
09:34

Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease

Published on: April 4, 2018

33.9K

Dissecting how ALS-associated D290V mutation enhances pathogenic aggregation of hnRNPA2286-291 peptides: Dynamics and

Yuan Tan1, Yujie Chen1, Xianshi Liu1

  • 1State Key Laboratory of Surface Physics, and Key Laboratory for Computational Physical Sciences (Ministry of Education), Department of Physics, Fudan University, Shanghai 200438, People's Republic of China.

International Journal of Biological Macromolecules
|April 29, 2023
PubMed

Insights

The D290V mutation in hnRNPA2 enhances peptide aggregation, a key factor in neurodegenerative diseases like ALS. This mutation increases peptide compactness and beta-sheet content, promoting disease-causing protein aggregation.

Area of Science:

  • Biochemistry
  • Neuroscience
  • Computational Biology

Background:

  • RNA binding proteins, including hnRNPA1/2, TDP-43, and FUS, are implicated in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS).
  • An ALS-related D290V mutation in the low complexity domain (LCD) of hnRNPA2 enhances the aggregation of hnRNPA2 peptides, but the molecular mechanisms are unclear.

Purpose of the Study:

  • To investigate the molecular mechanisms by which the D290V mutation affects the aggregation dynamics and conformational ensemble of hnRNPA2 peptides.
  • To elucidate the role of specific molecular interactions in mediating the enhanced aggregation propensity of the D290V mutant.

Main Methods:

  • All-atom molecular dynamic (MD) simulations.
  • Replica-exchange molecular dynamic (REMD) simulations were employed to explore the conformational landscape of hnRNPA2 peptides.

Main Results:

  • The D290V mutation significantly reduces the dynamics of the hnRNPA2 peptide.
  • Oligomers formed by the D290V mutant exhibit increased compactness and higher beta-sheet content compared to wild-type (WT) oligomers.
  • The D290V mutation strengthens inter-peptide hydrophobic interactions, main-chain hydrogen bonding, and side-chain aromatic stacking.

Conclusions:

  • The D290V mutation enhances the aggregation capability of hnRNPA2 peptides through increased compactness and specific intermolecular interactions.
  • These findings provide insights into the dynamics and thermodynamic mechanisms of D290V-induced aggregation in hnRNPA2 LCD.
  • Understanding these mechanisms is crucial for comprehending the transition of hnRNPA2 LCD from reversible condensates to irreversible pathogenic aggregates in ALS-related diseases.
Keywords:
Amyotrophic lateral sclerosisIrreversible pathogenic aggregationMolecular dynamics simulation

More Related Videos

Aip1p Dynamics Are Altered by the R256H Mutation in Actin08:57

Aip1p Dynamics Are Altered by the R256H Mutation in Actin

Published on: July 30, 2014

8.0K
Why Quantification Matters: Characterization of Phenotypes at the Drosophila Larval Neuromuscular Junction10:41

Why Quantification Matters: Characterization of Phenotypes at the Drosophila Larval Neuromuscular Junction

Published on: May 12, 2016

8.2K

Related Concept Videos

Amyloid Fibrils03:03

Amyloid Fibrils

Amyloid fibrils are aggregates of misfolded proteins.  Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils. 
Amyloid deposits were observed as early as 1639 in the liver and the spleen.   In 1854, Rudolph Virchow performed iodine staining,...
9.7K
Export of Misfolded Proteins out of the ER01:32

Export of Misfolded Proteins out of the ER

After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
3.7K
Protein Complex Assembly02:41

Protein Complex Assembly

Proteins can form homomeric complexes with another unit of the same protein or heteromeric complexes with different types.  Most protein complexes self-assemble spontaneously via ordered pathways, while some proteins need assembly factors that guide their proper assembly. Despite the crowded intracellular environment, proteins usually interact with their correct partners and form functional complexes.
Many viruses self-assemble into a fully functional unit using the infected host cell to...
10.7K