DNAJA2 and Hero11 mediate similar conformational extension and aggregation suppression of TDP-43 DOI Creative Commons
Andy Y.W. Lam, Kotaro Tsuboyama, Hisashi Tadakuma

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Nov. 15, 2022

Abstract Protein misfolding and aggregation are characteristic features of neurodegenerative diseases. While molecular chaperones well-known suppressors these aberrant events, we recently reported that highly disordered, hydrophilic charged heat-resistant obscure (Hero) proteins may have similar effects. Specifically, Hero can maintain the activity other from denaturing conditions in vitro, while their overexpression suppress cellular toxicity associated with aggregation-prone proteins. However, it is unclear how protective effects achieved. Here, utilized single-molecule FRET to monitor conformations prion-like low complexity domain (LCD) TAR DNA-binding protein 43 (TDP-43). observed high conformational heterogeneity wild-type LCD, ALS-associated mutation A315T promoted collapsed conformations. In contrast, an Hsp40 chaperone, DNAJA2, a protein, Hero11 stabilized extended states consistent ability TDP-43. Our results link on conformation macro bulk aggregation, where like integrity client prevent its aggregation.

Language: Английский

A coarse‐grained model for disordered and multi‐domain proteins DOI Creative Commons
Fan Cao, Sören von Bülow, Giulio Tesei

et al.

Protein Science, Journal Year: 2024, Volume and Issue: 33(11)

Published: Oct. 16, 2024

Many proteins contain more than one folded domain, and such modular multi-domain help expand the functional repertoire of proteins. Because their larger size often substantial dynamics, it may be difficult to characterize conformational ensembles by simulations. Here, we present a coarse-grained model for that is both fast provides an accurate description global properties in solution. We show accuracy one-bead-per-residue depends on how interaction sites domains are represented. Specifically, find excessive domain-domain interactions if located at position C

Language: Английский

Citations

17
GENESIS CGDYN: large-scale coarse-grained MD simulation with dynamic load balancing for heterogeneous biomolecular systems DOI Creative Commons
Jaewoon Jung, Cheng Tan, Yuji Sugita

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: April 20, 2024

Abstract Residue-level coarse-grained (CG) molecular dynamics (MD) simulation is widely used to investigate slow biological processes that involve multiple proteins, nucleic acids, and their complexes. Biomolecules in a large system are distributed non-uniformly, limiting computational efficiency with conventional methods. Here, we develop hierarchical domain decomposition scheme dynamic load balancing for heterogeneous biomolecular systems keep even after drastic changes particle distribution. These schemes applied the of intrinsically disordered protein (IDP) droplets. During fusion two droplets, find droplet shape correlate mixing IDP chains. Additionally, simulate achieving sizes comparable those observed microscopy. In our MD simulations, directly observe Ostwald ripening, phenomenon where small droplets dissolve molecules redeposit into larger methods have been implemented CGDYN GENESIS software, offering tool investigating mesoscopic using residue-level CG models.

Language: Английский

Citations

15
A coarse-grained model for disordered and multi-domain proteins DOI Creative Commons
Fan Cao, Sören von Bülow, Giulio Tesei

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 7, 2024

Abstract Many proteins contain more than one folded domain, and such modular multi-domain help expand the functional repertoire of proteins. Because their larger size often substantial dynamics, it may be difficult to characterize conformational ensembles by simulations. Here, we present a coarse-grained model for that is both fast provides an accurate description global properties in solution. We show accuracy one-bead-per-residue depends on how interaction sites domains are represented. Specifically, find excessive domain-domain interactions if located at position C α atoms. also centre mass residue, obtain good agreement between simulations experiments across wide range then optimize our previously described CALVADOS using this centre-of-mass representation, validate resulting independent data. Finally, use revised simulate phase separation disordered proteins, examine stability differ dilute dense phases. Our results provide starting point understanding regions these affect propensity self-associate undergo separation.

Language: Английский

Citations

11
DNAJA2 and Hero11 mediate similar conformational extension and aggregation suppression of TDP-43 DOI
Andy Y.W. Lam, Kotaro Tsuboyama, Hisashi Tadakuma

et al.

RNA, Journal Year: 2024, Volume and Issue: 30(11), P. 1422 - 1436

Published: Aug. 8, 2024

Many RNA-binding proteins (RBPs) contain low-complexity domains (LCDs) with prion-like compositions. These long intrinsically disordered regions regulate their solubility, contributing to physiological roles in RNA processing and organization. However, this also makes these RBPs prone pathological misfolding aggregation that are characteristic of neurodegenerative diseases. For example, TAR DNA-binding protein 43 (TDP-43) forms aggregates associated amyotrophic lateral sclerosis (ALS) frontotemporal lobar degeneration (FTLD). While molecular chaperones well-known suppressors aberrant events, we recently reported highly disordered, hydrophilic, charged heat-resistant obscure (Hero) may have similar effects. Specifically, Hero can maintain the activity other from denaturing conditions vitro, while overexpression suppress cellular toxicity aggregation-prone proteins. it is unclear how protective effects achieved. Here, used single-molecule FRET monitor conformations LCD TDP-43. observed high conformational heterogeneity wild-type LCD, ALS-associated mutation A315T promoted collapsed conformations. In contrast, an Hsp40 chaperone, DNAJA2, a protein, Hero11, stabilized extended states consistent ability Our results link on conformation macro bulk aggregation, where like integrity client prevent its aggregation.

Language: Английский

Citations

5
Aromatic and arginine content drives multiphasic condensation of protein-RNA mixtures DOI Creative Commons
Pin Yu Chew, Jerelle A. Joseph, Rosana Collepardo‐Guevara

et al.

Biophysical Journal, Journal Year: 2023, Volume and Issue: unknown

Published: July 1, 2023

Multiphasic architectures are found ubiquitously in biomolecular condensates and thought to have important implications for the organization of multiple chemical reactions within same compartment. Many these multiphasic contain RNA addition proteins. Here, we investigate importance different interactions comprising two proteins using computer simulations with a residue-resolution coarse-grained model RNA. We find that multilayered containing both phases, protein-RNA dominate, aromatic residues arginine forming key stabilizing interactions. The total content must be appreciably distinct phases form, show this difference increases as system is driven toward greater multiphasicity. Using trends observed interaction energies system, demonstrate can also construct preferentially concentrated one phase. “rules” identified thus enable design synthetic facilitate further study their function.

Language: Английский

Citations

13
The Regulation of TDP-43 Structure and Phase Transitions: A Review DOI

Yanqing Liu,

Jiani Xiang,

Hang Gong

et al.

The Protein Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 22, 2025

Language: Английский

Citations

0
No structure, no problem: Protein stabilization by Hero proteins and other chaperone-like IDPs DOI
Andy Y.W. Lam, Yukihide Tomari, Kotaro Tsuboyama

et al.

Biochimica et Biophysica Acta (BBA) - General Subjects, Journal Year: 2025, Volume and Issue: unknown, P. 130786 - 130786

Published: March 1, 2025

Language: Английский

Citations

0
Scaling molecular dynamics for large-scale simulation of biological systems on AMD CPU/GPU supercomputers: Lessons from LUMI DOI
Diego Ugarte La Torre, Jaewoon Jung, Yuji Sugita

et al.

Published: Feb. 19, 2025

Language: Английский

Citations

0
Nondomain biopolymers: Flexible molecular strategies to acquire biological functions DOI Creative Commons
Kazuharu Arakawa, Tetsuro Hirose, Toshifumi Inada

et al.

Genes to Cells, Journal Year: 2023, Volume and Issue: 28(8), P. 539 - 552

Published: May 30, 2023

A long-standing assumption in molecular biology posits that the conservation of protein and nucleic acid sequences emphasizes functional significance biomolecules. These conserved fold into distinct secondary tertiary structures, enable highly specific interactions, regulate complex yet organized processes within living cells. However, recent evidence suggests biomolecules can also function through primary sequence regions lack across species or gene families. typically do not form rigid their inherent flexibility is critical for roles. This review examines emerging roles mechanisms "nondomain biomolecules," whose functions are easily predicted due to absence domains. We propose hypothesis both domain- nondomain-type molecules work together flexible efficient crowded intracellular environment.

Language: Английский

Citations

8
Fusion Dynamics and Size-Dependence of Droplet Microstructure in ssDNA-Mediated Protein Phase Separation DOI Creative Commons
Yunqiang Bian,

Fangyi Lv,

Hai Pan

et al.

JACS Au, Journal Year: 2024, Volume and Issue: 4(9), P. 3690 - 3704

Published: Sept. 4, 2024

Biomolecular condensation involving proteins and nucleic acids has been recognized to play crucial roles in genome organization transcriptional regulation. However, the biophysical mechanisms underlying droplet fusion dynamics microstructure evolution during early stage of liquid-liquid phase separation (LLPS) remain elusive. In this work, we study linker histone H1, which is among most abundant chromatin proteins, presence single-stranded DNA (ssDNA) capable forming a G-quadruplex by using molecular simulations experimental characterization. We found that rather stochastic kinetically controlled process. Productive events are triggered formation ssDNA-mediated electrostatic bridges within contacting zone. The size-dependent evolves driven maximizing number contacts. also showed folding ssDNA promotes LLPS increasing multivalency strength protein-DNA interactions. These findings provide deep mechanistic insights into growth biomolecular droplets highlight key role kinetic control ssDNA-protein condensation.

Language: Английский

Citations

2