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ATP binds and inhibits the neurodegeneration-associated fibrillization of the FUS RRM domain.

ABSTRACT: Adenosine triphosphate (ATP) provides energy for cellular processes but has recently been found to act also as a hydrotrope to maintain protein homeostasis. ATP bivalently binds the disordered domain of FUS containing the RG/RGG sequence motif and thereby affects FUS liquid-liquid phase separation. Here, using NMR spectroscopy and molecular docking studies, we report that ATP specifically binds also to the well-folded RRM domain of FUS at physiologically relevant concentrations and with the binding interface overlapping with that of its physiological ssDNA ligand. Importantly, although ATP has little effect on the thermodynamic stability of the RRM domain or its binding to ssDNA, ATP kinetically inhibits the RRM fibrillization that is critical for the gain of cytotoxicity associated with ALS and FTD. Our study provides a previously unappreciated mechanism for ATP to inhibit fibrillization by specific binding, and suggests that ATP may bind additional proteins other than the classic ATP-dependent enzymes.

SUBMITTER: Kang J

PROVIDER: S-EPMC6586847 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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ATP binds and inhibits the neurodegeneration-associated fibrillization of the FUS RRM domain.

Kang Jian J Lim Liangzhong L Song Jianxing J

Communications biology 20190620

Adenosine triphosphate (ATP) provides energy for cellular processes but has recently been found to act also as a hydrotrope to maintain protein homeostasis. ATP bivalently binds the disordered domain of FUS containing the RG/RGG sequence motif and thereby affects FUS liquid-liquid phase separation. Here, using NMR spectroscopy and molecular docking studies, we report that ATP specifically binds also to the well-folded RRM domain of FUS at physiologically relevant concentrations and with the bind ...[more]

PMID: 31240261

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Project description:Amyotrophic lateral sclerosis (ALS) and frontotemporal lobe degeneration (FTLD) are two inter-related intractable diseases of motor neuron degeneration. Fused in sarcoma (FUS) is found in cytoplasmic accumulation of ALS and FTLD patients, which readily link the protein with the diseases. The RNA recognition motif (RRM) of FUS has the canonical α-β folds along with an unusual lysine-rich loop (KK-loop) between α1 and β2. This KK-loop is highly conserved among FET family proteins. Another contrasting feature of FUS RRM is the absence of critical binding residues, which are otherwise highly conserved in canonical RRMs. These residues in FUS RRM are Thr286, Glu336, Thr338, and Ser367, which are substitutions of lysine, phenylalanine, phenylalanine, and lysine, respectively, in other RRMs. Considering the importance of FUS in RNA regulation and metabolism, and its implication in ALS and FTLD, it is important to elucidate the underlying molecular mechanism of RNA recognition. In this study, we have performed molecular dynamics simulation with enhanced sampling to understand the conformational dynamics of noncanonical FUS RRM and its binding with RNA. We studied two sets of mutations: one with alanine mutation of KK-loop and another with KK-loop mutations along with critical binding residues mutated back to their canonical form. We find that concerted movement of KK-loop and loop between β2 and β3 facilitates the folding of the partner RNA, indicating an induced-fit mechanism of RNA binding. Flexibility of the RRM is highly restricted upon mutating the lysine residues of the KK-loop, resulting in weaker binding with the RNA. Our results also suggest that absence of the canonical residues in FUS RRM along with the KK-loop is equally important in regulating its binding dynamics. This study provides a significant structural insight into the binding of FUS RRM with its cognate RNA, which may further help in designing potential drugs targeting noncanonical RNA recognition.

Dataset Information

ATP binds and inhibits the neurodegeneration-associated fibrillization of the FUS RRM domain.

Publications

ATP binds and inhibits the neurodegeneration-associated fibrillization of the FUS RRM domain.

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