The structure of the mammalian nucleotide-sugar transporter mCST (colorful helices at the periphery), while bound to a nucleotide-sugar called CMP-sialic acid (yellow structure in the center). Image credits: Ahuja and Whorton (CC BY 4.0)
The cells in our body are tiny machines which, amongst other things, produce proteins. One of the production steps involves a compartment in the cell called the Golgi, where proteins are tagged and packaged before being sent to their final destination. In particular, sugars can be added onto an immature protein to help to fold it, stabilize it, and to affect how it works.
Before sugars can be attached to a protein, they need to be ‘activated’ outside of the Golgi by attaching to a small molecule known as a nucleotide. Then, these ‘nucleotide-sugars’ are ferried across the Golgi membrane and inside the compartment by nucleotide-sugar transporters, or NSTs. Humans have seven different kinds of NSTs, each responsible for helping specific types of nucleotide-sugars cross the Golgi membrane. Changes in NSTs are linked to several human diseases, including certain types of epilepsy; these proteins are also important for dangerous microbes to be able to infect cells. Yet, scientists know very little about how the transporters recognize their cargo, and how they transport it.
To shed light on these questions, Ahuja and Whorton set to uncover for the first time the 3D structure of a mammalian NST using a method known as X-ray crystallography. This revealed how nearly every component of this transporter is arranged when the protein is bound to two different molecules: a specific nucleotide, or a type of nucleotide-sugar. The results help to understand how changes in certain components of the NST can lead to a problem in the way the protein works. Ultimately, this knowledge may be useful to prevent diseases linked to faulty NSTs, or to stop microbes from using the transporters to their own advantage.
