A Phosphorylation-Induced Micellization Switch in the Low-Complexity Domain of TDP-43.

ABSTRACT: Phase separation (PS) of the low-complexity domain (LCD) of TAR DNA-binding protein 43 kDa (TDP-43) is linked to pathogenic aggregates in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). Here, we show that extensive phosphorylation of the LCD C-terminus redirects its self-assembly. Coarse-grained Monte Carlo simulations predicted that 12 Ser phosphorylations partition the 148-residue LCD into a hydrophobic N-terminal and highly charged C-terminal block, favouring finite-sized micellization over macroscopic PS. In vitro, LCD phosphorylated by casein kinase 1 delta (CK1δ; mean of 12 phosphorylations by native mass spectrometry) and phosphomimetic 12D/12DD mutants formed spherical nanoparticles (≈ 20-50 nm) above a low-micromolar critical micelle concentra

SUBMITTER: Dillenburg RF 

PROVIDER: S-EPMC13410809 | biostudies-literature | 2026 Oct

REPOSITORIES: biostudies-literature