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Cholesterol and Sugar Uptake Mechanisms

Periodic Reporting for period 4 - CSUMECH (Cholesterol and Sugar Uptake Mechanisms)

Reporting period: 2020-01-01 to 2020-12-31

Cardiovascular disease, diabetes and cancer have a dramatic impact on modern society, and in great part are related to uptake of cholesterol and sugar. At the start of this project, we still knew surprisingly little about the molecular details of the processes that goes on in this essential part of human basic metabolism. Our work has addressed cholesterol and sugar transport to elucidate the molecular mechanism of cholesterol and sugar uptake in humans and all eukaryotes. It aimed to move the frontiers of the field by shifting the focus to molecular studies in vitro allowing hitherto untried structural and biochemical experiments to be performed.

After the conclusion of the action, we have now shifted the frontiers significantly. We have elucidated the atomic details that pathway for sterol uptake in from lysosomes into the cellular membranes, and helped to pinpoint the mechanisms that govern this process. We have a deep and detailed understanding of sugar uptake, both in humans but also expanding to other eukaryotes, such as plants. The action has generated insights, based on the human sugar uptake system, that can have wide-ranging consequences for our ability model, control and argument sugar uptake in a range of organisms (humans, bacteria, plants).
Using structural biology methods we have published the binding mode of the human sugar transporter GLUT1 to important small-molecule inhibitors that have been used in research for decades. Furthermore these results gives clues towards new drug designs that could inhibit cellular sugar uptake.
We have published a model for sugar uptake and how this is regulated in humans and other sugar uptake systems in other organisms.
We have expanded on this to look at sugar uptake in plants and compare to the human system to understand the general mechanisms at play in this key pathway in eukaryotic metabolism.

Also using structural biology methods, we have elucidated how sterols are integrated into membranes via the action of a membrane protein NPC1/NCR1, using a hitherto undescribed tunnel to drive translocation of sterols past the glycocalyx. This result is a major breakthrough in the field and has been analyzed, and confirmed by numerous other groups afterwards.
A we are now at the end of the grant period, we can state that we have published a detailed description of how sugar is moved across cellular membranes, both in humans and other organisms. We have described novel regulatory mechanisms involved in sugar transport in molecular detail.
We have described the first detailed atomic description of how sterol are integrated into the cellular membrane using the NPC1/NPC2 homeostasis system, redefining the molecular transport models in the field.
sugar binding site in molecular detail