Department of Molecular Biology and Genetics, Aarhus University, Aarhus C, Denmark.
Department of Molecular Biology and Genetics, Aarhus University, Aarhus C, Denmark
Life Sci Alliance. 2021 Feb 3;4(4). doi: 10.26508/lsa.202000858. Print 2021 Apr.
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 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.
人葡萄糖转运蛋白 GLUT1 和 GLUT3 作为 Sugar Porter (SP) 家族的典型成员，在葡萄糖摄取中起着核心作用。GLUT1 和 GLUT3 具有完全保守的底物结合位点，具有相同的底物协调，但与它们的生理功能一致，在转运亲和力上有显著差异。在这里，我们呈现了一个 2.4 Å 的 GLUT1 内向开放构象的晶体结构，并使用结构和功能数据将其与 GLUT3 进行了比较。我们的工作表明，细胞质“SP 基序”和保守的“A 基序”之间的相互作用稳定了外向构象状态，并增加了底物的表观亲和力。此外，我们在 GLUT1 中鉴定了一个以前未描述的 Cl 离子结合位点和一个内侧面脂/葡萄糖结合位点，它们调节 GLUT 的动力学。研究结果为 GLUT1 和 GLUT3 葡萄糖亲和力的差异提供了一个可能的解释，暗示了 GLUT 动力学的一般调节模型，并为 SP 家族中定义的 SP 序列基序提供了一个生理功能。
