Tethering-induced destabilization and ATP-binding for tandem RRM domains of ALS-causing TDP-43 and hnRNPA1

Abstract TDP-43 and hnRNPA1 contain tandemly-tethered RNA-recognition-motif (RRM) domains, which not only functionally bind an array of nucleic acids, but also participate in aggregation/fibrillation, a pathological hallmark various human diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), alzheimer's disease (AD) Multisystem proteinopathy (MSP). Here, by DSF, NMR MD simulations we systematically characterized stability, ATP-binding conformational dynamics RRM domains both tethered isolated forms. The results reveal three key findings: (1) upon tethering become dramatically coupled destabilized with Tm reduced to 49 °C. (2) ATP specifically binds occupies the similar pockets within conserved nucleic-acid-binding surfaces, affinity slightly higher than (3) indicate that have Two as shown characterization analysis inter-domain correlation motions. study explains long-standing puzzle RRM1–RRM2 is particularly prone underscores general role inhibiting aggregation/fibrillation RRM-containing proteins. rationalize observation risk aggregation-causing increases aging.