The proteinopathy of D169G and K263E mutants at the RNA Recognition Motif (RRM) domain of tar DNA-binding protein (tdp43) causing neurological disorders: A computational study

Abstract

One of the multitasking proteins, transactive response DNA-binding protein 43 (tdp43) plays a key role in RNA regulation and the two pathogenic mutations such as D169G and K263E, located at the RNA Recognition Motif (RRM) of tdp43, are reported to cause neurological disorders such as Amyotrophic Lateral Sclerosis and FrontoTemporal Lobar Degeneration. As the exploration of the proteinopathy demands both structural and functional characterizations of mutants, a comparative analysis on the wild type and mutant tdp43 (D169G and K263E) and their complexes with RNA has been performed using computational approaches. Molecular dynamics simulations revealed comparatively stable mutant structures compared to wild type tdp43. Both mutants show lesser binding affinity toward RNA molecule when compared to the wild type tdp43. Some of the observed features, including the increased solvent-accessible surface area, conformational flexibility as well as unfolding of tdp43, and the altered RNA conformation in tp43-RNA complex, reveal the susceptibility of these mutants to induce conformational changes in tdp43 for a possible aggregation in the cytoplasm. Particularly, the enhanced aggregation propensity of both mutants also evidences the higher probability of cytoplasmic aggregation of tdp43 mutants. Hence, the present analysis highlighting the structural and functional aspects of wild and mutant tdp43 will form the basis to gain insight into the proteinopathy of tdp43 and the related structure-based drug discovery. Thus, tdp43 can be used as target to develop novel therapeutic approaches or drug designing.

Differential binding affinity of tau repeat region R2 with neuronal-specific β-tubulin isotypes

“…In NPT, all these heated systems were equilibrated using the Parrinello-Rahman barostat for 1 ns to maintain constant pressure of 1 bar. The unrestrained production MD simulations were performed for 100 ns over all the tubulin-TauR2 complexes using parameters discussed in our earlier study 59 . The long range electrostatic interactions were treated with particle mesh Ewald (PME) method 60,61 and covalent bonds involving H-atoms were constrained using the ‘LINCS’ algorithm 62 .…”

The role of ubiquitinated TDP-43 in amyotrophic lateral sclerosis

“…These changes also brought the enhanced aggregation propensity in the cytoplasm [28] . These novel findings were important to illustrate the mechanism in the structural and functional aspects of ALS development.…”

Aggregation of the nucleic acid–binding protein TDP-43 occurs via distinct routes that are coordinated with stress granule formation

“…Consistent with a role for this modification in disease, acetylated TDP-43 was detected in ALS patient spinal cord harboring full-length TDP-43 but was not present in FTLD-TDP brain containing mostly cleaved C-terminal TDP-43 fragments that lack the Lys-145 residue (10). We proposed that aberrantly acetylated TDP-43 triggers its aggregation in a similar manner to genetic TARDBP mutations, some of which also reside within the RNA recognition motif domains and potentially modulate critical interactions between TDP-43 and target mRNA (11,12). TDP-43 acetylation was most prominent when TDP-43 was targeted to the cytoplasm, prompting us to consider its role in cytoplasmic mRNA triage.…”