Mechanism of Serotonin Transport in Human Brain

Diwakar Shukla, University of Illinois at Urbana-Champaign

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Diwakar Shukla, Alexander Moffett, Zahra Shamsi, Balaji Selvam, Chuankai Zhao, Shriyaa Mittal, Jiangyan Feng, Jiming Chen, Matthew Chan, Faisal Aldukhi, Pouyan Khakbaz, Soumajit Dutta, Austin Weigle, Prateek Bansal

Monoamine transporters are transmembrane proteins localized at the plasma membrane of neurons, involved in reuptake of neurotransmitters in the synaptic cleft. Transporter proteins adopts three different conformational states, the outward facing, occluded and inward facing states, to transport neurotransmitters into the cell. Hence, it is important to understand the structural transition between these states to fully comprehend the functional mechanism of transporters.

We will investigate the serotonin transporter (SERT) which selectivity reuptakes and transports serotonin. A recent crystal structure of hSERT provides the first glimpse of this key transporter in nerve cells. However, the mechanistic basis of substrate recognition, binding and transport-driven structural rearrangements remained elusive. We propose to (a) perform extensive simulations of SERT using Blue Waters Supercomputer to explore the conformational landscape of the protein, (b) elucidate the mechanism of the regulation of the activity via phosphorylation and dimerization and validate it experimentally.