Aromatic and aliphatic residues of the disordered region of TDP-43 are on a fast track for self-assembly

Biochem Biophys Res Commun. 2021 Sep 20;578:110-114. doi: 10.1016/j.bbrc.2021.09.040. Online ahead of print.ABSTRACTThe C-terminal, intrinsically disordered, prion-like domain (PrLD) of TDP-43 promotes liquid condensate and solid amyloid formation. These phase changes are crucial to the normal biological functions of the protein but also for its abnormal aggregation, which is implicated in amyotrophic lateral sclerosis (ALS) and certain dementias. We and other previously found that certain amyloid forms emerge from an intermediate condensed state that acts as a nucleus for fibrillization. To quantitatively ascertain the role of individual residues within TDP-43's PrLD in its early self-assembly we have followed the kinetics of NMR 1H-15N HSQC signal loss to obtain values for the lag time, elongation rate and extent of condensate formation at equilibrium. The results of this analysis represent a robust corroboration that aliphatic and aromatic residues are key drivers of condensate formation.PMID:34560580 | DOI:10.1016/j.bbrc.2021.09.040

Source: Biochemical and Biophysical Research communications - September 24, 2021 Category: Biochemistry Authors: Douglas V Laurents Cristiana Stuani David Pantoja-Uceda Emanuele Buratti Miguel Mompe án Source Type: research