隨遇而安
人生境遇不可選擇，心態可以選擇
It appears to me that the questions raised by Runtao Yan below center on the genesis of figure 5 and the unique contributions to the transport mechanism by Dr. NiengYan’s team.
On the genesis of Figure 5.
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At the most superficial level, figure 7 of Iancu et al. (cited by this paper) reveals that the basic scheme of figure 5 was not created out of a vacuum by the authors of this paper. It is not surprising to see that a glucose transporter would follow the Alternate Access Model (AAM) as its principle transport mechanism.
As Forrest described in his review of the secondary active transport mechanisms, secondary transporters, MFS family proteins in particular, share this basic principle of Alternate Access. A cursory survey of past literature, also revealed numerous papers with similar schematic depiction of the Alternating Access by MFS proteins (Dang, Forrest, Guan, Iancu, Madej, Nie) , some of which are cited by this paper. The diagrams in some of these papers are even more detailed than Figure 5. For example, Forrest proposed an 8-state model which includes the four state model in this paper. It seems to me that it was common knowledge in this field at the time that MFS family member proteins carry out their transport duties through AAM, and no reasonable person would have mistakenly taken the entire Figure 5 as Dr. Nieng Yan’s own creation.
While there are nuanced differences in transport mechanisms by different MFS proteins, the focus of current research was not whether these membrane transporters utilize alternate access mechanism but the way by which alternate access is realized in common (e.g. Rocker Switch vs Gating Pore).
As to the biochemical data, I believe they are from Sun 2012 as quoted in the figure legend, referring to figure 5b in particular, demonstrating the essential nature of ICH in the Figure, the importance of which is mentioned below.
On the unique contributions by this paper.
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After a close examination of Figure 5, one would not have missed the combination of the rocker switch and the gating pore mechanisms mentioned in Forrest et al., confirming the negotiation of these two seemingly contradictory mechanisms in LeuT. One would also not have missed the unique feature of the intracellular gate ICH of Glut 1 and XylE and possibly other MFS family 1 proteins, likely found nowhere else in the literature except Sun 2012 and this paper. I would remiss if I did not also mention the intricate interplays of extracellular gate and ICH in directing the back and forth exchange between the inward and outward conformations of Glut1, XylE and other MFS family 1 member proteins, again would have been kept in the dark without Dr.Nieng Yan's work.
A well trained scientist cannot fail to appreciate the detailed comparisons between uniporters and symporters, including proton coupling in the discussion, aided by the detailed structural knowledge at the molecular level rendered only by analyses of crystal structures at this time.
Let me conclude with a quote from Forrest on the importance of crystal structure in elucidating the transport mechanism: “Currently the most stimulating contribution to our understanding of secondary transport is the fast growing amount of structural data on transport proteins. This impact is particular significant when crystal structures are available for a given transporter in different states”. This paper has certainly made a most stimulating contribution to our understanding of the transport mechanism and more importantly, of the various diseases caused by Glut1 deficiencies, which could lead to breakthroughs in medical treatments of these diseases. Many patients in the future might unknowingly owe tribute to this paper. I am sure Dr Nieng Yan would not mind this innocuous omission.
References
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Dang, S. et al. Structure of a fucose transporter in an outward-open conformation. Nature 467, 734–738 (2010).
Forrest et al. The structural basis of secondary active transport mechanisms Biochimica et Biophysica Acta 1807 (2011) 167–188
Guan and Kaback: Lessons from Lactose Permease. Annu Rev Biophys Biomol Struct. 2006 ; 35: 67–91.
Iancu, C. V., Zamoon, J., Woo, S. B., Aleshin, A. & Choe, J. Y. Crystal structure of a glucose/H1 symporter and its mechanismof action. Proc. Natl Acad. Sci. USA 110, 17862–17867 (2013).
Madej, M. G., Sun, L., Yan, N. & Kaback, H. R. Functional architecture of MFS D-glucose transporters. Proc. Natl Acad. Sci. USA 111, E719–E727 (2014).
Nie, Y., et al. Energetics of Ligand-induced Conformational Flexibility in the Lactose Permease of Escherichia coli J Biol Chem. 2006 November 24; 281(47): 35779–35784
Sun, L. et al. Crystal structure of a bacterial homologue of glucose transporters GLUT1–4. Nature 490, 361–366 (2012).
謝謝美言：）
我覺得隻是在Super和Fox之間少了一個空格而已，還不至於公然欺騙雜誌和吃瓜群眾吧？生活在美國這樣重視誠信的社會，這點最基本的黨悟還是應該有的。否則如何安身立命，生活下去。
It appears to me that the issues raised by Runtao Yan are centering on Figure 5 which demonstrates the unique contributions of Nieng Yan team to the transport mechanism of glucose through membranes.
A. On the genesis of Figure 5
Iancu et al. (cited in this paper; their Figure 7) revealed a basic scheme for Figure 5 that a glucose transporter follows the Alternate Access Model (AAM). Forrest (reference please) reviewed that active transport mechanisms by secondary transporters, in particular proteins in the MFS family, also share the basic principle of AAM. Numerous other papers (Dang, Forrest, Guan, Iancu, Madej, Nie) depicted similarly that MFS proteins follow the AAM. Some of these papers illustrated the AAM in even more details than Figure 5, for example, Forrest proposed an eight-state model which has even included the four-state model demonstrated in this paper.
It thus appears to be a common knowledge that MFS family proteins transport glucose by the AAM mechanism. Figure 5 is by no means accredited entirely to Nieng Yan team. Nevertheless, the current research has disclosed (or confirmed?) how the AAM is realized (e.g. Rocker Switch vs Gating Pore).
The biochemical data questioned by Runtao should be referred to Sun 2012, as quoted in the caption of Figure 5b. In fact, Figure 5 demonstrates the essential nature of the ICH as a unique contribution by this paper.
B. ICH is the unique contribution
A close inspection of Figure 5 indicates a combination of the rocker switch and gating pore mechanisms, as reviewed (discussed?) in Forrest et al.; it also confirms the negotiation of the two seemly contradictory mechanisms in LeuT (reference please). Figure 5 also indicates the unique feature of the intracellular gate ICH of Glut 1 and XylE, which occurs in other MFS family-1 proteins, as disclosed by Sun 2012 and this paper. The intricate interplay of the extracellular gate and ICH directs the back-forth exchange between the inward and outward conformations of Glut1, XylE and other MFS family-1 proteins.
Forrest has recognized the importance of crystal structures in elucidating the transport mechanism: “Currently the most stimulating contribution to our understanding of secondary transport is the fast growing amount of structural data on transport proteins. This impact is particular significant when crystal structures are available for a given transporter in different states”. The crystal structure in this paper has made a stimulating contribution to our understanding of the transport mechanism. It is potentially useful to attack various diseases caused by Glut1 deficiencies.
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多謝二位美言 ：）