Journal Article

Structure and mechanism of the mammalian fructose transporter GLUT5

Kang, Hae Joo, Verdon, Grégory, Hussien, Saba Abdul, Shimamura, Tatsuro, Sonoda, Yo, Kasahara, Michihiro, Sato, Yumi, Coincon, Mathieu, Nomura, Yayoi, Kusano-Arai, Osamu, Nakada-Nakura, Yoshiko, Murata, Takeshi, Nomura, Norimichi, Qureshi, Aziz Abdul, Abe, Hitomi, Iwanari, Hiroko, Kobayashi, Takuya, Arakawa, Takatoshi, Drew, David, Iwata, So, Hino, Tomoya, Hamakubo, Takao

2015

Overview

The altered activity of the fructose transporter GLUT5, an isoform of the facilitated-diffusion glucose transporter family, has been linked to disorders such as type 2 diabetes and obesity. GLUT5 is also overexpressed in certain tumour cells, and inhibitors are potential drugs for these conditions. Here we describe the crystal structures of GLUT5 from Rattus norvegicus and Bos taurus in open outward- and open inward-facing conformations, respectively. GLUT5 has a major facilitator superfamily fold like other homologous monosaccharide transporters. On the basis of a comparison of the inward-facing structures of GLUT5 and human GLUT1, a ubiquitous glucose transporter, we show that a single point mutation is enough to switch the substrate-binding preference of GLUT5 from fructose to glucose. A comparison of the substrate-free structures of GLUT5 with occluded substrate-bound structures of Escherichia coli XylE suggests that, in addition to global rocker-switch-like re-orientation of the bundles, local asymmetric rearrangements of carboxy-terminal transmembrane bundle helices TM7 and TM10 underlie a ‘gated-pore’ transport mechanism in such monosaccharide transporters. This study has determined the X-ray crystal structures of GLUT5 from Rattus norvegicus in an open, outward-facing conformation and GLUT5 from Bos taurus in an open, inward-facing conformation; comparison of these structures with previously published structures of the related Escherichia coli d -xylose:H + symporter XylE suggests that transport in GLUT5 is controlled by both a global ‘rocker-switch’-type motion and a local ‘gated-pore’-type transport mechanism. Structure of fructose transporter GLUT5 SLC2 family glucose transporters (GLUTs) facilitate the transport of glucose and other monosaccharides across biological membranes. GLUT5, which is fructose-specific, has been linked to disorders such as type 2 diabetes and obesity and is overexpressed in certain tumour cells. The authors solve X-ray crystal structures of GLUT5 from the brown rat in an open, outward-facing conformation and GLUT5 from cattle in an open, inward-facing conformation. Comparison of these structures with previously published structures of the related XylE, a proton-coupled sugar transporter from Escherichia coli , suggest that transport in GLUT5 is controlled by both 'rocker-switch' and 'gated-pore' type transport mechanisms. Also in this issue of Nature , Dong Deng et al . solve the X-ray crystal structures of human GLUT3 in outward-open and outward-occluded conformations.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/535/1266 / 631/92/577 / 82/1 / 82/16 / 82/80 / 82/83 / Animals / Asymmetry / Binding Sites / Biochemistry / biokemi / Biological Transport / Carrier proteins / Cattle / Cell Membrane - metabolism / Crystallography, X-Ray / E coli / Escherichia coli - chemistry / Escherichia coli Proteins - chemistry / Escherichia coli Proteins - metabolism / Fructose - chemistry / Fructose - metabolism / Glucose / Glucose - chemistry / Glucose - metabolism / Glucose Transporter Type 1 - chemistry / Glucose Transporter Type 1 - metabolism / Glucose Transporter Type 5 - chemistry / Glucose Transporter Type 5 - genetics / Glucose Transporter Type 5 - metabolism / Humanities and Social Sciences / Mammals / Models, Molecular / Molecular biology / Molecular structure / multidisciplinary / Mutation / Physiological aspects / Point Mutation - genetics / Protein Conformation / Rats / Salts - chemistry / Science / Static Electricity / Structure / Structure-Activity Relationship / Substrate Specificity - genetics / Symporters - chemistry / Symporters - metabolism