Structural basis for the delivery of activated sialic acid into Golgi for sialyation

Abstract

The decoration of secretory glycoproteins and glycolipids with sialic acid is critical to many physiological and pathological processes. Sialyation is dependent on a continuous supply of sialic acid into Golgi organelles in the form of CMP-sialic acid. Translocation of CMP-sialic acid into Golgi is carried out by the CMP-sialic acid transporter (CST). Mutations in human CST are linked to glycosylation disorders, and CST is important for glycopathway engineering, as it is critical for sialyation efficiency of therapeutic glycoproteins. The mechanism of how CMP-sialic acid is recognized and translocated across Golgi membranes in exchange for CMP is poorly understood. Here we have determined the crystal structure of a eukaryotic CMP-sialic acid transporter in complex with CMP. We conclude that the specificity of CST for CMP-sialic acid is established by the nucleotide CMP to such an extent, they are uniquely able to work both as passive and as (secondary) active antiporters.