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- W2912556867 abstract "Glutamate is the most important excitatory neurotransmitter in the human brain. Its concentration controls synaptic transmission, thus maintaining low concentration of glutamate in the synapse is of critical importance. The synaptic concentration of glutamate in mammalian brain is regulated by excitatory amino acid transporter-1 (EAAT1), which harvests the energy of sodium, proton, and potassium gradients to uptake glutamate from the synapse. The transport mechanism involves outward-facing (OF) to inward-facing (IF) conformational changes of EAAT1, where glutamate is transported from the extracellular to the intracellular region. EAAT1 is reported to partition into cholesterol-rich regions of the membrane, suggesting that cholesterol might play an important role in its function. Each monomer of EAAT1 consists of two distinct domains, the trimerization domain and the transport domain. The interconversion between the two can be described as nearly a rigid body movement of the transport domain in lipid bilayer with respect to the trimerization domain, following an elevator-like motion, involving both translational and orientational components. In this study we have performed extensive all-atom simulations of recently crystalized human EAAT1 in cholesterol-rich and cholesterol-free lipid-bilayers. Our results suggest that compared to the modeled POPC membranes, the cholesterol-rich bilayer modifies the orientational dynamics of EAAT1, which we attribute to the increased lateral pressure of the lipid bilayer. Distribution of lipids around the protein shows cholesterol binding to the interface between the trimerization and transport domains of EAAT1. A combination of equilibrium simulations, string calculations and 1D-BEUS free energy calculations demonstrate that cholesterol has a high affinity towards the interface and alters the OF-IF transitions in EAAT1. Remarkably, the same interface forms the binding pocket for an allosteric inhibitor UCPH, thus we suggest cholesterol might play an important role in governing the dynamics and kinetics of EAAT1." @default.
- W2912556867 created "2019-02-21" @default.
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- W2912556867 date "2019-02-01" @default.
- W2912556867 modified "2023-09-26" @default.
- W2912556867 title "Modulation of Orientational Dynamics of Excitatory Amino Acid Transporter-1 by Cholesterol" @default.
- W2912556867 doi "https://doi.org/10.1016/j.bpj.2018.11.2990" @default.
- W2912556867 hasPublicationYear "2019" @default.
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