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bioRxiv · 10.1101/2020.02.24.962258

Structural comparative analysis of GLUT1 and GLUT3 reveal role of SP motif in transport regulation

Custodio, T. F.·Paulsen, P. A.·Pedersen, B. P.
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Abstract

The human glucose transporters GLUT1 and GLUT3 have a central role in glucose uptake as canonical members of the Sugar Porter (SP) family. GLUT1 and GLUT3 share a fully conserved substrate-binding site with identical substrate coordination, but differ significantly in transport affinity in line with their physiological function. Here we present a 2.4 [A] crystal structure of GLUT1 in an inward open conformation and compare it with GLUT3 using both structural and functional data. Our work shows that interactions between a cytosolic "Sugar Porter motif" and a conserved "A motif" stabilize the outward conformational state and increases substrate apparent affinity. Furthermore, we identify a previously undescribed Cl- ion site in GLUT1 and an endofacial lipid/glucose binding site which modulate GLUT kinetics. The results provide a possible explanation for the difference between GLUT1 and GLUT3 glucose affinity, imply a general model for the kinetic regulation in GLUTs and suggest a physiological function for the defining SP sequence motif in the Sugar Porter family. Summary BlurbNew structure of GLUT1 compared to GLUT3 explain different substrate affinities. The result provide a functional rationale for key structural motifs that define the universal Sugar Porter family.

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Custodio, T. F., Paulsen, P. A., Pedersen, B. P.. 2020-02-26. Structural comparative analysis of GLUT1 and GLUT3 reveal role of SP motif in transport regulation. https://doi.org/10.1101/2020.02.24.962258

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