Author:
Sarkar Susmita,Gupta Saurabh,Mahato Chiranjit,Das Dibyendu,Mondal Jagannath
Abstract
AbstractProteins occurring in significantly high concentrations in cellular environments (over 100 mg/mL) and functioning in crowded cytoplasm, often face the prodigious challenges of aggregation which are the pathological hallmark of aging and are critically responsible for a wide spectrum of rising human diseases. Adenosine triphosphate (ATP), apart from its conventional activity as energy carrier, has been recently reported to play crucial roles in cellular protein homeostasis involving stabilization of soluble proteins and solubilization of insoluble candidates for driving different biological processes. However, the potential role of ATP in modulating structural plasticity of the insoluble proteins and its probable link with ATP’s solubilizing effect have escaped the mainstream investigation. Here we first computationally simulate how ATP influences the conformational landscape of globular mini-protein Trp-cage and intrinsically disordered protein Aβ40, which are situated at mutually opposite ends of the structural spectrum. Subsequently a joint-venture of complementary wet-lab experiments and computer simulation pin-points that ATP enhances protein solubility by unwinding protein chains via direct ATP-protein preferential interaction in a protein-specific manner and prevents condensation of aggregation-prone Aβ40 as well as promotes dissolution of pre-formed aggregates. Our study also establishes the superiority of ATP as a solubilizer of protein aggregate over traditional chemical hydrotrope (NaXS) and highlights promising potential implications and ATP-based therapeutic interventions in protein-aggregation related diseases.
Publisher
Cold Spring Harbor Laboratory