A novel mechanism for ATP to enhance the functional oligomerization of TDP-43 by specific binding.


Department of Biological Sciences, Faculty of Science, National University of Singapore, 10 Kent Ridge Crescent, 119260, Singapore. Electronic address: [Email]


Pathological TDP-43 aggregation has been found in ∼98% ALS and other neurodegenerative diseases including Alzheimer's. TDP-43 N-terminal domain (NTD) was recently shown to form a tubular super-helical filament by oligomerization in vivo, which functions to prevent its pathological aggregation. ATP, the universal energy currency with very high concentrations in all living cells, was recently decoded to act as a biological hydrotrope to maintain protein homeostasis. Here by NMR spectroscopy, we reveal for the first time that at physiological concentrations ATP binds the TDP-43 NTD to enhance its oligomerization. Most strikingly, this binding is specifically coupled with oligomerization because three mutants with the capacity of oligomerization eliminated lose the ability to bind ATP. Our study thus provides a novel mechanism for ATP to prevent pathological aggregation by specific binding; and further implies that ATP might have many previously-unknown functions in cells by binding to proteins other than the classic ATP-dependent proteins/enzymes.


Adenosine triphosphate (ATP),Amyotrophic lateral sclerosis (ALS),Frontotemporal dementia (FTD),NMR spectroscopy,TDP-43 N-Terminal domain (NTD),

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