Youngki You1, Joydip Das1. 1. From the Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas.
Abstract
BACKGROUND: EtOH has a significant effect on synaptic plasticity. Munc13-1 is an essential presynaptic active zone protein involved in priming the synaptic vesicle and releasing neurotransmitter in the brain. It is a peripheral membrane protein and binds to the activator, diacylglycerol (DAG)/phorbol ester at its membrane-targeting C1 domain. Our previous studies identified Glu-582 of C1 domain as the alcohol-binding residue (Das, J. et al, J. Neurochem., 126, 715-726, 2013). METHODS: Here, we describe a 250 ns molecular dynamics (MD) simulation study on the interaction of EtOH and the activator-bound Munc13-1 C1 in the presence of varying concentrations of phosphatidylserine (PS). RESULTS: In this study, Munc13-1 C1 shows higher conformational stability in EtOH than in water. It forms fewer hydrogen bonds with phorbol 13-acetate in the presence of EtOH than in water. EtOH also affected the interaction between the protein and the membrane and between the activator and the membrane. Similar studies in a E582A mutant suggest that these effects of EtOH are mostly mediated through Glu-582. CONCLUSIONS: EtOH forms hydrogen bonds with Glu-582. While occupancy of the EtOH molecules at the vicinity (4Å) of Glu-582 is 34.4%, the occupancy in the E582A mutant is 26.5% of the simulation time. In addition, the amount of PS in the membrane influences the conformational stability of the C1 domain and interactions in the ternary complex. This study is important in providing the structural basis of EtOH's effects on synaptic plasticity.
BACKGROUND:EtOH has a significant effect on synaptic plasticity. Munc13-1 is an essential presynaptic active zone protein involved in priming the synaptic vesicle and releasing neurotransmitter in the brain. It is a peripheral membrane protein and binds to the activator, diacylglycerol (DAG)/phorbol ester at its membrane-targeting C1 domain. Our previous studies identified Glu-582 of C1 domain as the alcohol-binding residue (Das, J. et al, J. Neurochem., 126, 715-726, 2013). METHODS: Here, we describe a 250 ns molecular dynamics (MD) simulation study on the interaction of EtOH and the activator-bound Munc13-1C1 in the presence of varying concentrations of phosphatidylserine (PS). RESULTS: In this study, Munc13-1C1 shows higher conformational stability in EtOH than in water. It forms fewer hydrogen bonds with phorbol 13-acetate in the presence of EtOH than in water. EtOH also affected the interaction between the protein and the membrane and between the activator and the membrane. Similar studies in a E582A mutant suggest that these effects of EtOH are mostly mediated through Glu-582. CONCLUSIONS:EtOH forms hydrogen bonds with Glu-582. While occupancy of the EtOH molecules at the vicinity (4Å) of Glu-582 is 34.4%, the occupancy in the E582A mutant is 26.5% of the simulation time. In addition, the amount of PS in the membrane influences the conformational stability of the C1 domain and interactions in the ternary complex. This study is important in providing the structural basis of EtOH's effects on synaptic plasticity.
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Authors: Francisco A Blanco; Agnes Czikora; Noemi Kedei; Youngki You; Gary A Mitchell; Satyabrata Pany; Anamitra Ghosh; Peter M Blumberg; Joydip Das Journal: Biochemistry Date: 2019-06-20 Impact factor: 3.162