Article: The physical forces mediating self-association and phase-separation in the C-terminal domain of TDP-43
BBA - Proteins and Proteomics. 2017,
2017
Abstract: The TAR DNA-binding protein of 43kDa (TDP-43) has been identified as the main component of amyotrophic lateral sclerosis (ALS) cytoplasmic inclusions. The link between this proteinopathy and TDP-43â²s intrinsically disordered C-terminal domain is well ... ...
| Abstract | The TAR DNA-binding protein of 43kDa (TDP-43) has been identified as the main component of amyotrophic lateral sclerosis (ALS) cytoplasmic inclusions. The link between this proteinopathy and TDP-43â²s intrinsically disordered C-terminal domain is well known, but recently also, this domain has been shown to be involved in the formation of the membraneless organelles that mediate TDP-43â²s functions. The mechanisms that underpin the liquid-liquid phase separation (LLPS) of these membraneless organelles undergo remain elusive. Crucially though, these factors may be the key to understanding the delicate balance between TDP-43â²s physiological and pathological functions. In this study, we used nuclear magnetic resonance spectroscopy and optical methods to demonstrate that an α-helical component in the centre (residues 320â340) of the C-terminal domain is related to the protein's self-association and LLPS. Systematically analysing ALS-related TDP-43 mutants (G298S, M337V, and Q331K) in different buffer conditions at different temperatures, we prove that this phase separation is driven by hydrophobic interactions but is inhibited by electrostatic repulsion. Based on these findings, we rationally introduced a mutant, W334G, and demonstrate that this mutant disrupts LLPS without disturbing this α-helical propensity. This tryptophan may serve as a key residue in this protein's LLPS. |
|---|---|
| Keywords | amino acid sequences ; amyotrophic lateral sclerosis ; cytoplasmic inclusions ; DNA-binding proteins ; electrostatic interactions ; hydrophobic bonding ; mutants ; nuclear magnetic resonance spectroscopy ; organelles ; separation ; temperature ; tryptophan |
| Language | English |
| Size | p. . |
| Publishing place | Elsevier B.V. |
| Document type | Article |
| Note | Pre-press version |
| ZDB-ID | 2918798-9 |
| ISSN | 1878-1454 ; 1570-9639 |
| ISSN (online) | 1878-1454 |
| ISSN | 1570-9639 |
| DOI | 10.1016/j.bbapap.2017.10.001 |
| Database | NAL-Catalogue (AGRICOLA) |
Full text online
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
| Zs.A 7161: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG) |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.