Nucleotide sugar transporters

Glycosylation is a fundamental cellular process that, in eukaryotes, occurs in the lumen of both the Golgi apparatus and the endoplasmic reticulum. Nucleotide sugar transporters (NSTs) are an essential component of the glycosylation pathway, providing the diverse range of substrates required for the glycosyltransferases.

Nucleotide sugar transporters selectively move activated suagr molecules into the Golgi and ER lumen.

NSTs belong to the SLC35 family of solute carriers, and their function is highly conserved from simple eukaryotes, fungi and parasites to plants and mammals. NSTs are among only a small number of transporters implicated in Mendelian diseases, such as leukocyte adhesion deficiency II, caused by point mutations within the transporter specific for GDP–fucose, and congenital disorder of glycosylation IIf, caused by mutations in the CMP–sialic acid transporter.

The transport of nucleotide sugars into the secretory pathway is also important for pathogenic fungi and trypanosomatid parasites, as these organisms contain a cell wall or a surface glycocalyx predominantly consisting of glycomannosylated conjugates that form a protective coat against the human immune system. In these organisms, GDP–mannose transport is fundamental for virulence, making NSTs attractive targets for inhibitor design.

Recently we determined the first crystal structure for a member of the SLC35 transporter family, the GDP-mannose transporter Vrg4. The GDP-mannose bound structure revealed two specificity pockets for binding the nucleotide and sugar groups respectively.

Crystal structure of Vrg4 bound to substrate, GDP-Mannose.

A hitherto unobserved requirement of short-chain lipids in activating the transporter supports a model for regulation within the highly dynamic membranes of the Golgi apparatus.

Our results provide a structural basis for understanding nucleotide sugar recognition, and provide insights into the transport and regulatory mechanism of this family of intracellular transporters.