Abstract
Recent studies have suggested that synphilin-1, a cytoplasmic protein, is involved in energy homeostasis. Overexpression of synphilin-1 in neurons results in hyperphagia and obesity in animal models. However, the mechanism by which synphilin-1 alters energy homeostasis is unknown. Here, we used cell models and biochemical approaches to investigate the cellular functions of synphilin-1 that may affect energy balance. Synphilin-1 was pulled down by ATP-agarose beads, and the addition of ATP and ADP reduced this binding, indicating that synphilin-1 bound ADP and ATP. Synphilin-1 also bound GMP, GDP, and GTP but with a lower affinity than it bound ATP. In contrast, synphilin-1 did not bind with CTP. Overexpression of synphilin-1 in HEK293T cells significantly increased cellular ATP levels. Genetic alteration to abolish predicted ATP binding motifs of synphilin-1 or knockdown of synphilin-1 by siRNA reduced cellular ATP levels. Together, these data demonstrate that synphilin-1 binds and regulates the cellular energy molecule, ATP. These findings provide a molecular basis for understanding the actions of synphilin-1 in energy homeostasis.
Highlights
Synphilin-1 is a cytoplasmic protein with 919 amino acids [1]
Synphilin-1 interacts with asynuclein, parkin, leucine-rich repeat kinase-2 (LRRK2), other ubiquitin ligases, and proteasome subunit/regulators, and has been shown to be associated with
Given the similar functions between ATP and GTP, we only studied the relationship between synphilin-1 and ATP/ADP in the below experiments
Summary
Synphilin-1 is a cytoplasmic protein with 919 amino acids [1]. The biological functions of synphilin-1 are not fully understood [2]. Synphilin-1 contains ankyrin-like repeats and a coiled-coil domain, and harbors predicted ATP binding motifs [1, 3]. Human synphilin-1 is expressed in various tissues and its expression is enriched in the brain [3,4,5]. Several studies suggest that synphilin-1 may be of relevance to Parkinson’s disease (PD) pathology. Synphilin-1 interacts with asynuclein, parkin, leucine-rich repeat kinase-2 (LRRK2), other ubiquitin ligases, and proteasome subunit/regulators, and has been shown to be associated with
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