Paper Title
Novel Mechanisms for ATP to Control Protein Homeostasisby Specific Binding

Abstract
ATP is bestknown as the universal energy currency which has very high concentrations (~2-12 mM) in all living cells. Only recently, ATP was decoded to act as a biological hydrotrope to maintain protein homeostasis. Very recently we investigated the roles of ATP in liquid-liquid phase separation (LLPS) and protein amyloid fibrillation of TDP-43 and FUS domains whose pathological aggregation is a hallmark of various neurodegenerative diseases including Amyotrophic lateral sclerosis (ALS), Frontotemporal dementia (FTD)and Alzheimer's by NMR spectroscopy. NMR is very powerful in not only detecting, but also obtaining residue-specific binding parameters for the extremely weak binding events. We unexpectedly found that: 1) ATP acts as a bivalent binder to induce at low concentrations but at high concentrations dissolve LLPS of the intrinsically-disordered FUS RGG domain. 2) ATP can specifically bind and kinetically inhibit the amyloid formation of the FUS RRM domain. 3) ATP can specifically bind the TDP-43 N-terminal domain (NTD) to enhance its functional oligomerization, thus antagonizing the pathological aggregation of TDP-43. Our studies revealed that at concentrations > mM, in addition to acting as a biological hydrotrope,ATP can also play critical roles in human aging and diseases by specifically binding many previously-unknown protein domains.