Structural features of the glutamate transporter family

Neuronal and glial glutamate transporters remove the excitatory neurotransm itter glutamate fi om the synaptic cleft and thus prevent neurotoxicity The proteins belong to a large and widespread family of secondary transporters , including bacterial glutamate, serine, and C-4-dicarboxylate transporters ; mammalian neutral-amino-acid transporters; and an increasing number of ba cterial archaeal, and eukaryotic proteins that have not yet been functional ly characterized Sixty members of the glutamate transporter family,cere fou nd ill the databases on the basis of sequence homology. The amino acid sequ ences of the carriers have diverged enormously. Homology between the member s of the family is most apparent in a stretch of approximately 150 residues in the C-terminal part of the proteins. This region contains four reasonab ly well-conserved sequence motifs, all of which have been suggested to be p art of the translocation pore or substrate binding site. Phylogenetic analy sis of the C-terminal stretch revealed the presence of five subfamilies wit h characterized members: (i) the eukaryotic glutamate transporters, (ii) th e bacterial glutamate transporters, (iii) the eukaryotic neutral-amino-acid transporters, (iv) the bacterial C-4-dicarboxylate transporters, and (v) t he bacterial serine transporters. A number of other subfamilies that do not contain characterized members have been defined. In contrast to their amin o acid sequences, the hydropathy profiles of the members of the family are extremely well conserved. Analysis of the hydropathy profiles has suggested that the glutamate transporters have a global structure that is unique amo ng secondary transporters Experimentally, the unique structure of the trans porters was recently confirmed by membrane topology studies. Although there is still controversy about part of the topology, the most likely model pre dicts the presence of eight membrane-spanning alpha-helices and a loop-pore structure which is unique among secondary transporters brit may resemble l oop-pores found in ion channels. A second distinctive structural feature is the presence of a highly amphipathic membrane-spanning helix that provides a hydrophilic path through the membrane. Recent data from analysis of site -directed mutants and studies on the mechanism and pharmacology of the tran sporters are discussed in relation to the structural model.