4.6 Article

Structural comparison of GLUT1 to GLUT3 reveal transport regulation mechanism in sugar porter family

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LIFE SCIENCE ALLIANCE
卷 4, 期 4, 页码 -

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LIFE SCIENCE ALLIANCE LLC
DOI: 10.26508/lsa.202000858

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  1. European Research Council [637372]
  2. Novo Nordisk Foundation [NNF17OC0026900]
  3. Carlsberg Foundation [CF17-0180]
  4. Jeppe Juhl and wife Ovita Juhls Memorial Fund
  5. Aarhus Institute of Advanced Studies (AIAS) fellowship
  6. European Research Council (ERC) [637372] Funding Source: European Research Council (ERC)

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The study compared the structures and functional data of GLUT1 and GLUT3, revealing significant differences in glucose affinity between them, possibly due to interactions between the cytosolic SP motif and conserved A motif. Additionally, previously undescribed Cl- ion site and endofacial lipid/glucose binding site in GLUT1 were identified as modulators of GLUT kinetics.
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 angstrom 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 SP 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 SP family.

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