Back to search

FRIMEDBIO-Fri prosj.st. med.,helse,biol

Structural studies of the full-length human Vitamin C transporters: unravelling Vitamin C transport across the membrane

Alternative title: Strukturelle studier av full-lengde humane C-vitamin-transportører: C-vitamin transport over membraner

Awarded: NOK 8.0 mill.

Sodium-dependent Vitamin C Transporters, part of the large solute carrier protein family and responsible for Vitamin C uptake and regulation are known to be fundamental for healthy immune function. Importantly, high levels of Vitamin C has been linked to decrease mortality in COVID-19 patients with sepsis-related Acute Respiratory Disease Syndrome shock. Abnormal Vitamin C regulation has been also associated with several diseases, including cancer, obesity, hypertension, autoimmune and neurodegenerative diseases. Furthermore, Vitamin C attenuates oxidative stress caused by alcohol consumption while continuous Vitamin C deficiency leads to scurvy. Despite their importance, Vitamin C uptake and regulation are poorly understood. In humans, there two classes of such Vitamin C transporters that are phosphorylation-dependent glycoproteins with an overall 65% sequence identity. Specifically, one class is expressed on the epithelia of hepatic, intestinal and renal tissues, presenting low affinity and high capacity for Vitamin C, having an important role in regulation of whole body homeostasis. Another class, exhibits high affinity and low capacity, and is expressed in most cells and tissues where its function is the delivery of Vitamin C to cells as a cofactor for major enzyme pathways protecting from oxidative stress. To date, the structural basis for the mechanism of action of these transporters remains largely unexplored. Here, we aim at unraveling the mechanism of Vitamin C transport and regulation by determining the three-dimensional structures of classes thereby providing mechanistic understanding of the different activities of these transporters. We will use a multidisciplinary approach of high-resolution cryo-electron microscopy, X-ray crystallography and biophysical methods to understand the transporters function and interactions. This work will contribute to elucidating the mechanism of Vitamin C transport and ultimately lead to drug discovery.

SVCTs are Sodium-dependent Vitamin C Transporters, part of the large solute carrier protein family (SLC) and responsible for Vitamin C uptake and regulation, known to be fundamental for healthy immune function. Importantly, high levels of Vitamin C has been linked to decrease mortality in COVID-19 patients with sepsis-related Acute Respiratory Disease Syndrome (ARDS) shock. Abnormal Vitamin C regulation has been also associated with several diseases, including cancer, obesity, hypertension, autoimmune and neurodegenerative diseases. Furthermore, Vitamin C attenuates oxidative stress caused by alcohol consumption while continuous Vitamin C deficiency leads to scurvy. Despite their importance, Vitamin C uptake and regulation are poorly understood. In humans, SVCTs include two classes, SVCT1 and SVCT2, that are phosphorylation-dependent glycoproteins with an overall 65% sequence identity. Specifically, SVCT1 is expressed on the epithelia of hepatic, intestinal and renal tissues, presenting low affinity and high capacity for Vitamin C, having an important role in regulation of whole body homeostasis. SVCT2, on the other hand, exhibits high affinity and low capacity, and is expressed in most cells and tissues where its function is the delivery of Vitamin C to cells as a cofactor for major enzyme pathways protecting from oxidative stress. To date, the structural basis for the mechanism of action of SVCTs remains largely unexplored. Here, we aim at unraveling the mechanism of Vitamin C transport and regulation by determining the three-dimensional structures of both SVCT1 and SVCT2, thereby providing mechanistic understanding of the different activities of these transporters. We will use a multidisciplinary approach of high-resolution cryo-electron microscopy, X-ray crystallography and biophysical methods to understand SVCT function and interactions. This work will contribute to elucidating the mechanism of Vitamin C transport by SVCTs and ultimately lead to drug discovery.

Activity:

FRIMEDBIO-Fri prosj.st. med.,helse,biol