ABSTRACT
Disrupted-in-schizophrenia-1 (DISC1) is a scaffold protein that plays a pivotal role in orchestrating signaling pathways involved in neurodevelopment, neural migration, and synaptogenesis. Among those, it has recently been reported that the role DISC1 in the Akt/mTOR pathway can shift from a global translational repressor to a translational activator in response to oxidative stress induced by arsenic. In this study we are providing evidence that DISC1 can directly bind arsenic via a C-terminal cysteine motif (C-X-C-X-C). A series of fluorescence-based binding assays were conducted with a truncated C-terminal domain construct of DISC1 and a of series of single, double, and triple cysteine mutants. We found that arsenous acid, a trivalent arsenic derivative, specifically binds to the C-terminal cysteine motif of DISC1 with low micromolar affinity. All three cysteines of the motif are required for high-affinity binding. Electron microscopy experiments combined with in silico structural predictions revealed that that the C-terminal of DISC1 forms an elongated tetrameric complex. The cysteine motif is consistently predicted to be located within a loop, fully exposed to solvent, providing a simple molecular framework to explain the high-affinity of DISC1 toward arsenous acid. This study sheds light on a novel functional facet of DISC1 as an arsenic binding protein and highlights its potential role as both a sensor and translational modulator within the Akt/mTOR pathway.
ABSTRACT
Disrupted-in-schizophrenia-1 (DISC1) is a scaffolding protein that plays a pivotal role in orchestrating signaling pathways involved in neurodevelopment, neural migration, and synaptogenesis. Among those, it has recently been reported that the role of DISC1 in the Akt/mTOR pathway can shift from a global translational repressor to a translational activator in response to oxidative stress induced by arsenic. In this study we provide evidence that DISC1 can directly bind arsenic via a C-terminal cysteine motif (C-X-C-X-C). A series of fluorescence-based binding assays were conducted with a truncated C-terminal domain construct of DISC1 and a series of single, double, and triple cysteine mutants. We found that arsenous acid, a trivalent arsenic derivative, specifically binds to the C-terminal cysteine motif of DISC1 with low micromolar affinity. All three cysteines of the motif are required for high-affinity binding. Electron microscopy experiments combined with in silico structural predictions reveal that the C-terminal of DISC1 forms an elongated tetrameric complex. The cysteine motif is consistently predicted to be located within a loop, fully exposed to solvent, providing a simple molecular framework to explain the high-affinity of DISC1 toward arsenous acid. This study sheds light on a novel functional facet of DISC1 as an arsenic binding protein and highlights its potential role as both a sensor and translational modulator within Akt/mTOR pathway.
ABSTRACT
5,10,15,20-Tetraphenylporphyrin chromium chloride (TPPCrCl) with added [Ph3PâNâPPh3](+)Cl(-) (PPN(+)Cl(-)) selectively polymerizes lactide (L and rac) dissolved in neat propylene oxide (PO) to yield polylactide (PLA) terminated by the -OCHMeCH2Cl group. At 0 °C and below, rac-LA yields polymers highly enriched in isotactic tetrads (iii). At 25 °C, some stereoselectivity is lost as transesterification becomes significant, and at 60 °C and above, enchainment of PO leads to the formation of 3,6-dimethyl-1,4-dioxan-2-one by a backbiting mechanism. At 0 °C, after the enchainment of L-(S,S)-LA in neat (R)-(+)-PO, the formation of (3S,6R)-3,6-dimethyl-1,4-dioxan-2-one occurs, while at higher temperatures the ratio of (3S,6R)-3,6-dimethyl-1,4-dioxan-2-one to (3R,6R)-3,6-dimethyl-1,4-dioxan-2-one falls to 3:2.
Subject(s)
Chromium/chemistry , Dioxanes/chemistry , Epoxy Compounds/chemistry , Metalloporphyrins/chemistryABSTRACT
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