Crystal structure of the human glucose transporter GLUT1
Authors: Nieng Yan
Chao Xu
Pengcheng Sun
Jianping Wu
Dong Deng
Mingxu Hu
Chuangye Yan
Journal: Nature (2014)
Discipline: Multidisciplinary
Keywords: GLUT1; glucose transporter; facilitative diffusion; erythrocytes; glucose supply
Affiliations: 1] State Key Laboratory of Bio-membrane and Membrane Biotechnology, Tsinghua University, Beijing 100084, China [2] Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China [3] Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China [4]., 1] State Key Laboratory of Bio-membrane and Membrane Biotechnology, Tsinghua University, Beijing 100084, China [2] Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China [3]., 1] State Key Laboratory of Bio-membrane and Membrane Biotechnology, Tsinghua University, Beijing 100084, China [2] Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China., 1] State Key Laboratory of Bio-membrane and Membrane Biotechnology, Tsinghua University, Beijing 100084, China [2] Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China [3] Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China.

Abstract:  The glucose transporter GLUT1 catalyses facilitative diffusion of glucose into erythrocytes and is responsible for glucose supply to the brain and other organs. Dysfunctional mutations may lead to GLUT1 deficiency syndrome, whereas overexpression of GLUT1 is a prognostic indicator for cancer. Despite decades of investigation, the structure of GLUT1 remains unknown. Here we report the crystal structure of human GLUT1 at 3.2 Å resolution. The full-length protein, which has a canonical major facilitator superfamily fold, is captured in an inward-open conformation. This structure allows accurate mapping and potential mechanistic interpretation of disease-associated mutations in GLUT1. Structure-based analysis of these mutations provides an insight into the alternating access mechanism of GLUT1 and other members of the sugar porter subfamily. Structural comparison of the uniporter GLUT1 with its bacterial homologue XylE, a proton-coupled xylose symporter, allows examination of the transport mechanisms of both passive facilitators and active transporters. 

Retracted: No

PubPeer comments:
 Comments Section of this paper on nature website: https: www.nature.com articles nature13306?page=3 , 
 Runtao Yan u2022 7 days ago u2022 edited Dear Nature, I am writing to you with a concern about Dr. Nieng Yan, a Member of the U.S. National Academy of Sciences (NAS). I believe she is guilty of scientific misconduct, and I have evidence to prove it. 1.Misleading the scientific community---- latch gate theory In the paper, she identified a u201clatchu201d which was one of her two main findings, and she thoroughly explained her latch gate finding (the other main finding was u201cthe Glut1 working modelu201d). In Fig.3 and Fig. 5, she named it a ICH domain and explained the ICH domain function as: u201cThe ICH domain serves as a latch that tightens the intracellular gate.u201d(p.123) u201cBecause of the extensive interactions between TMD and ICH, the ligand-free protein may prefer an outward-open conformation.u201d (p.124) In fact, the XylE and Glut1 are transporters belonging to the Facilitated Diffusion Superfamily, whose function (direction and efficiency) solely depends on the substrate concentration gradient across the membrane, and functionally no sided-ness. This means the glucose can be transported from one side of the membrane to the other and vice versa. It is impossible for a u201cfacilitated diffusion transporteru201d to have a u201cLATCH GATEu201d to maintain the out-facing direction. If so, they are no longer u201cDiffusion Transporters.u201d Instead, they are u201cGATED CHANNELS.u201d If Dr. Nieng Yanu2019s u201coutward-open latchu201d theory was true, then the glucose transporters COULD NOT RELEASE accumulated glucose into the extracellular space adjacent to the blood capillary, because the u201cLatch Gateu201d would make the transporter bear outward-open conformation with the inside closed by the latch, so that the glucose inside could not get into the translocation pathway of the transporter. In nature, glucose transporters DO release accumulated glucose into the extracellular space adjacent to the blood capillary by facilitated diffusion. In addition, if the latch had no function, then it should have been eliminated during the 3 billion years of transporter evolution. Apparently, Dr. Nieng Yan never did a biochemical assay for any Facilitated Diffusion Superfamily transporters and merely assumed that the glucose was transported only from outside to inside of the cells, and that the glucose concentration inside was always lower than outside, thus devising an artificial u201coutward-open conformation latch gateu201d theory without any scientific data to support it. The reviewers should have caught that, because in the paper, she mentioned that the XylE and Glut1 are members of the facilitated diffusion superfamily. She found the ICH latch domain from a crystallized symporter (XylE), and she predicted that u201csubstrate-free uniporters have a preferred open conformationu201d (P.124), which means that all of the uniporters should no longer be u201cFacilitated Diffusion Superfamilyu201d members. How can such an illogical and unrealistic u201ctheoryu201d, without any biochemical analysis or any scientific data support, be accepted by Nature reviewers, thus misleading the scientific community? I donu2019t know the answer. However, if I were to guess, I can imagine two possibilities. (A) Some reviewers may not be in the transporter field and have never done any biochemical assay in order to know that the facilitated diffusion transporters functionally have no sidedness, and therefore these reviewers just trusted Dr Nieng Yan. (B). A reviewer might have been in the transporter field, and perhaps, this reviewer might have been reluctant to challenge Dr. Nieng Yanu2019s scientific work, due to fear of losing funding from the Chinese government by collaboration. 2.Fooling the scientific community The u201cfour conformational structuresu201d described in the paper to prove her major scientific contribution cannot prove the working model. When the transporter (also called carrier) was in occluded inward-facing conformation (which means a glucose molecule was inside the transporter), Dr. Nieng Yan presented it as evidence that the glucose had entered the transporter from inside the cell (see Fig 5). However, the glucose could have been transported from outside the cell during crystallization. That is why we have to use radioactive labeled substrates in our experiments [Runtao Yan Peter C Maloney (JHU),1993 Cell, 75:37-44; 1995 PNAS, 92:5973-5976]. A simple example can illustrate this point. Suppose I show a picture of a man on a boat on the north bank of a river, and then assert that the man had boarded the boat from the north bank, a skeptic could question my inference, since the man might have ferried from the south to the north bank. Does this represent Dr. Nieng Yanu2019s level of logical thinking, or is she being deliberately deceptive? She should know that her u201cfour conformational structuresu201d cannot prove the working model of a transporter. How could she possibly ascertain whether the glucose was from the inside the cell, or transported from outside? It would be impossible for her to distinguish without radioactively labeling the substrate. 3.Deceiving and fabricating Even if the u201cfour-conformation structuresu201d proposed in the paper could prove that to be the working model of a transporter (which, in fact it could not), Dr. Nieng Yan did not find the four structures. In her paper, she claimed that the four structures are required for a complete transport cycle. However, there are only two crystal structures of E. coli xylose transporter (proton co-transporter, i.e. symporter), and one human glucose transporter Glut-1(uniporter). Even after combining the symporter and uniporter together, she only obtained THREE structures. When she presented u201cA working model of Glut1u201d (which were very bold words!) from Fig. 5, her conclusion was based on the u201cPredicted datau201d from Fig 5u2019s detailed descriptions (small words) . In other words, her work should be presented as a u201cPredicted working model of Glut1u201d instead of an actual u201cworking model of Glut1u201d. The essence of this wording is deceptive. It is impossible for Dr. Nieng Yan to propose a working model for Glut1 while lacking the basic experimentation of the u201cfour conformation structureu201d cycle. She clearly stated in her paper that (1) u201cthe conformational switch from inward-facing to outward-facing of symporters remains to be elucidatedu201d; and (2) The outward-open structure remains to be captured. 4.Not disclosing the source of the u201cpublished biochemical datau201d Since she did not obtain four crystal structures and had no way to identify the working model based on only three structures, she tried to fix the problem by providing more u201cevidenceu201d in her discussion section, where she said, u201cOn the basis of our structural analysis and published biochemical data, we propose a working model for Glut1u201d (P124 ). If she thought she did not need to provide appropriate references because the biochemical experiments were done in her lab, then she should not have used the term u201cPredictedu201d in Fig.5. No matter who may ultimately have performed the experiment, the fact is that the cystine-scan method created by RuntaoYan Peter C Maloney was the only biochemical method to identify the membrane transport working model (1995 PNAS, 92:5973-5976). , 
 The paper identified a u201clatchu201d which was one of the two main findings, and it thoroughly explained the latch gate finding (the other main finding was u201cthe Glut1 working modelu201d). In Fig.3 and Fig. 5, the paper named it a ICH domain and explained the ICH domain function as: u201cThe ICH domain serves as a latch that tightens the intracellular gate.u201d(p.123) u201cBecause of the extensive interactions between TMD and ICH, the ligand-free protein may prefer an outward-open conformation.u201d (p.124) In fact, the XylE and Glut1 are transporters belonging to the Facilitated Diffusion Superfamily, whose function (direction and efficiency) solely depends on the substrate concentration gradient across the membrane, and functionally no sided-ness. This means the glucose can be transported from one side of the membrane to the other and vice versa. It is impossible for a u201cfacilitated diffusion transporteru201d to have a u201cLATCH GATEu201d to maintain the out-facing direction. If so, they are no longer u201cDiffusion Transporters.u201d Instead, they are u201cGATED CHANNELS.u201d If the paper s u201coutward-open latchu201d theory was true, then the glucose transporters COULD NOT RELEASE accumulated glucose into the extracellular space adjacent to the blood capillary, because the u201cLatch Gateu201d would make the transporter bear outward-open conformation with the inside closed by the latch, so that the glucose inside could not get into the translocation pathway of the transporter. In nature, glucose transporters DO release accumulated glucose into the extracellular space adjacent to the blood capillary by facilitated diffusion. ,