PT  - JOURNAL ARTICLE
AU  - Tânia Filipa Custódio
AU  - Peter Aasted Paulsen
AU  - Kelly May Frain
AU  - Bjørn Panyella Pedersen
TI  - Structural comparison of GLUT1 to GLUT3 reveal transport regulation mechanism in Sugar Porter family
AID  - 10.1101/2020.02.24.962258
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2020.02.24.962258
4099  - http://biorxiv.org/content/early/2021/01/13/2020.02.24.962258.short
4100  - http://biorxiv.org/content/early/2021/01/13/2020.02.24.962258.full
AB  - 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 Å 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 Blurb New 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.Competing Interest StatementThe authors have declared no competing interest.