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

TY - JOUR

T1 - Structural comparison of GLUT1 to GLUT3 reveal transport regulation mechanism in sugar porter family

AU - Custódio, Tânia Filipa

AU - Paulsen, Peter Aasted

AU - Frain, Kelly May

AU - Pedersen, Bjørn Panyella

PY - 2021/4

Y1 - 2021/4

N2 - 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 “SP motif” and a conserved “A motif” stabilize the outward conformational state and increases substrate apparent affinity. Furthermore, we identify a previously undescribed Cl 2 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.

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 “SP motif” and a conserved “A motif” stabilize the outward conformational state and increases substrate apparent affinity. Furthermore, we identify a previously undescribed Cl 2 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.

UR - http://www.scopus.com/inward/record.url?scp=85101221248&partnerID=8YFLogxK

U2 - 10.26508/lsa.202000858

DO - 10.26508/lsa.202000858

M3 - Journal article

C2 - 33536238

AN - SCOPUS:85101221248

SN - 2575-1077

VL - 4

JO - Life Science Alliance

JF - Life Science Alliance

IS - 4

M1 - e202000858

ER -