Structural studies on SCL6A15 neutral amino acid transporter

Transporters from the SLC6 family play many important physiological functions. They are responsible for transport of neurotransmitters, osmolytes or energy substrates thus they participate in the nerve signaling and maintaining cellular and organism homeostasis. Depending on the sequence identity SLC6 family is divided into 4 groups: monoamine transporters, GABA transporters, amino acid transporters group I, and transporters for amino acids group II named also orphan transporters (OTs). OTs include 6 proteins, products of genes SLC6A15-SLCA620, whose 3D structures still remain unsolved (with one exception - SLC6A19).Their primary physiological function is supplying cells with nutritional neutral amino acids throughout sodium coupled symport. SLC6A15 (alias B(0)AT2) is mainly expressed in central nervous system. It allows for the transport of proline, branched-chain amino acids or methionine from extracellular compartment to the cell. Studies showed evidence that impaired functioning of SLC6A15 can be associated with major depressive disorder, behavioral changes or obesity. Since significance of SLC6A15 in the course of mentioned illnesses was proved we conducted preliminary in silico investigation to construct spatial structure of mentioned transporter using homology modeling. Further, we made an attempt to provide principles of substrate selectivity and functioning of the transporter. Using solved structures of the transporters for serotonin, dopamine, leucine (SERT, DAT, LeuT) and SCL6A19 we generated reliable models of SLC6A15 and performed docking studies. Obtained results showed significant role of hydrophobic pocket and non-helical fragments of TM6 and TM1 for binding of substrates.