Nucleotide Sugar Transporter SLC35 Family Structure and Function

The covalent attachment of sugars to growing glycan chains is heavily reliant on a specific family of solute transporters (SLC35), the nucleotide sugar transporters (NSTs) that connect the synthesis of activated sugars in the nucleus or cytosol, to glycosyltransferases that reside in the lumen of the endoplasmic reticulum (ER) and/or Golgi apparatus. This review provides a timely update on recent progress in the NST field, specifically we explore several NSTs of the SLC35 family whose substrate specificity and function have been poorly understood, but where recent significant progress has been made. This includes SLC35 A4, A5 and D3, as well as progress made towards understanding the association of SLC35A2 with SLC35A3 and how this relates to their potential regulation, and how the disruption to the dilysine motif in SLC35B4 causes mislocalisation, calling into question multisubstrate NSTs and their subcellular localisation and function. We also report on the recently described first crystal structure of an NST, the SLC35D2 homolog Vrg-4 from yeast. Using this crystal structure, we have generated a new model of SLC35A1, (CMP-sialic acid transporter, CST), with structural and mechanistic predictions based on all known CST-related data, and includes an overview of reported mutations that alter transport and/or substrate recognition (both de novo and site-directed). We also present a model of the CST-del177 isoform that potentially explains why the human CST isoform remains active while the hamster CST isoform is inactive, and we provide a possible alternate access mechanism that accounts for the CST being functional as either a monomer or a homodimer. Finally we provide an update on two NST crystal structures that were published subsequent to the submission and during review of this report.