Talk:WikiJournal of Science/ShK toxin: history, structure and therapeutic applications for autoimmune diseases

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<meta name='citation_doi' value='10.15347/wjs/2018.003'>

Article information

Authors: Shih Chieh Chang[i], Saumya Bajaj, K. George Chandy



Plagiarism check[edit]

Artículo bueno.svg Pass. Report from WMF copyvio tool using TurnItIn. Short phrases such as "...experimental autoimmune encephalomyelitis in rats, a model for multiple sclerosis" were similarly used in external pages, but not regarded as plagiarism. T.Shafee(Evo﹠Evo)talk 11:09, 9 January 2018 (UTC)

Reader Comments[edit]

Would it be possible for the authors to include a section on compliance with ethical standards to the end of this manuscript. A suitable section for this paper would be (if there are indeed no conflicts of interest and no studies with human or animal subjects):

Compliance with Ethical Standards
Conflicts of Interest
Shih Chieh Chang has not declared any potential conflits of interest
Saumya Bajaj has not declared any potential conflits of interest
K. George Chandy has not declared any potential conflits of interest
Human and animal Subjects
This article does not contain any studes with human or animal subjects performed by any of the authors

Van Vlijmen (discusscontribs) 07:06, 15 February 2018 (UTC)

First peer review[edit]

Preprint - ShK toxin history, structure and therapeutic applications for autoimmune diseasesHW.pdf

A


Reviewer-annotated pdf file.

Review by Heike Wulff  
This review was submitted on 2018-03-06, and refers to this previous version of the article

Overall this is a very well written and carefully prepared review and as a reviewer I only have a couple of minor stylistic and formatting comments to improve the clarity of the text.

1) History: The dash between ShK-170/ShK- 186 is confusing since these are two different peptides. It would be better to write “ShK-170 and ShK-186, two selective blockers of Kv1.3”. This is also more in line with the two separate references that are given. We have made the recommended change.

Response
We have made the recommended change.

The new sentence reads: “In 2005-2006, George Chandy and Christine Beeton at the University of California Irvine, USA, and Michael Pennington at Bachem Biosciences, USA, developed ShK-170 and ShK-186, selective blockers of Kv1.3.(19,20) ShK-186, now called Dalazatide, was advanced to human trials in 2015-2017 by Shawn Iadonato and Eric Tarcha at KPI Therapeutics, Seattle, USA, as the first-in-man Kv1.3 blocker for autoimmune disease.(45)

2) Structure: “….two short a-helices comprising” should be alpha-helices or α-helices

Response
We have made the recommended change.

The new sentence reads: “In 2005-2006, George Chandy and Christine Beeton at the University of California Irvine, USA, and Michael Pennington at Bachem Biosciences, USA, developed ShK-170 and ShK-186, selective blockers of Kv1.3.(19,20) ShK-186, now called Dalazatide, was advanced to human trials in 2015-2017 by Shawn Iadonato and Eric Tarcha at KPI Therapeutics, Seattle, USA, as the first-in-man Kv1.3 blocker for autoimmune disease.(45)


3) I am not sure that the section “Phylogenetic relationships of ShK and ShK domains” really is very useful for the general Wikipedia reader. The authors might want consider removing this section

Response
We respectfully disagree with the reviewer and believe that the section on phylogenetic relationships between ShK and ShK domains is of interest to the scientific community, especially to those who attend meetings such as the Gordon Research Conference on “Venom Evolution, Function and Biomedical Applications.” We would like to retain it in the article.

4) Efficacy of ShK: I would suggest to remove the following sentence and citation. Allograft transplant: Immunosuppressant drugs are used to prevent the rejection of transplanted organs. In a rat allograft renal transplant model, the combination of ShK and the KCa3.1 inhibitor TRAM-34 was as effective as cyclosporine A, a drug used clinically to prevent rejection of transplanted organ(s2.4) This study only went out for 14 days in a chronic rejection model that should have been taken out for 3 months. It does demonstrate some efficacy but the way this sentence is worded it would be very easy to misinterpret it for lay readers. As a reviewer I would highly recommend to remove it.

Response
We agree with the reviewer, and have removed the entire section titled “Allograft transplant.”

5) Functions of ShK-like domains in proteins This section again might not be very useful for the general Wikipedia reader.

Response
We think that the section on the function of ShK-like domains in proteins might help the readers understand the importance of the ShK-like domains in a diverse range of functions. We would like to retain it in the article. 

Conflict of Interest: The reviewer, Heike Wulff, was a postdoctoral researcher with K. George Chandy from 1999 to 2003 and has co-authored multiple publications with him.

Second peer review[edit]

Review by anonymous peer reviewer  
This review was submitted on 2018-05-10, and refers to this previous version of the article

The authors provide a nice summary of the ShK toxin, including its history and theraputic advancments and developments over the years. My concerns are mostly minor as the majority of the manuscript is extremely well written and the authors did a good job summarizing everything.

My minor concerns are focused on the History, Structure, and Phylogenetics section.

HISTORY

1. The sentences:

  • "Stichodactyla helianthus is a sea anemone of the family Stichodactylidae. Helianthus comes from the Greek words Helios meaning sun, and anthos meaning flower. S. helianthus is also referred to as the 'sun anemone"

would read better if revised, such as:

  • "Stichodactyla helianthus is a species of sea anemone (Cnidaria) belonging to the family Stichodactylidae. Helianthus comes from the Greek words Helios meaning sun, and anthos meaning

flower, which corresponds to S. helianthus common name "sun anemone."

Response
The suggested change has been made.

The new sentences now read: “Stichodactyla helianthus is a species of sea anemone (Cnidaria) belonging to the family Stichodactylidae. Helianthus comes from the Greek words Helios meaning sun, and anthos meaning flower, which corresponds to S. helianthus common name "sun anemone."

2. The statement: "It is sessile and uses potent neurotoxins for defense against its primary predator, the spiny lobster." needs a citation

Response
We have included a citation "Norton R, Pennington MW, Wulff H, Current Medicinal Chemistry, 2004, 11, 3041-3052" for the statement.

3. All of the people and associated institutions should be consistent throughout. (i.e. William Kem institution not mentioned, if it's UF make that clear). Also many of these people are not at these institutions currently, it may be confusing to readers if you do not specify that they were at these places at that time. Overall, I think it might be best to just remove the associated institutions as interested readers can see their locations from the citations used.

Response
We have removed the names of associated institutions.

STRUCTURE

4. The sentence: "The formula of ShK is C169H274N54O48S7." is not needed in my opinion.

Response
We have removed the sentence, as recommended.

5. The sentence: "Figure 3 shows the three-dimensional structure of ShK with key residues highlighted. Also included in the figure are structures of related peptides" would read better as: "Figure 3 shows the three-dimensional structure of ShK with key residues, in addition to the structures of related peptides"

Response
We have made the suggested modification

6. comma after "(from the filarial worm),"

Response
We have included a comma.

PHYLOGENETICS

7. An access date needs to be added to the EMBL numbers as these numbers may change over time.

Response
We have included an access date (May 2018)

8. There is certainly a lot worth expanding on in relation to the metallopeptidases being associated with ShK domains as the two may be working synergistically The citations you include 25-29 should allow you to expand on this topic a bit more. I don't think that this is absolutely necessary, but the authors should consider as it would provide some great information here and reflect the depth seen from the other sections of this manuscript.

Response
We have expanded the section on MMP-23. The new section now reads:

MMP-23 belongs to the family of zinc- and calcium-dependent matrix metalloproteases. It is anchored in the cell membrane by an N-terminal prodomain, and it contains three extracellular domains: catalytic metalloprotease domain, ShK domain and immunoglobulin-like cell adhesion molecule (Ig-CaM) domain.(25-29) The prodomain traps the voltage-gated potassium channel KV1.3, but not the closely related KV1.2 channel, in the endoplasmic reticulum.(25-29)  Studies with chimeras suggest that the prodomain interacts with the KV1.3 region from the S5 transmembrane segment to the C terminus.(24-28) NMR studies of the prodomain reveal a single trans-membrane alpha-helix, joined by a short linker to a juxta-membrane alpha-helix, which is associated with the surface of the membrane.(25-29) The prodomain shares topological similarity with proteins (KCNE1, KCNE2, KCNE4) known to trap potassium channels in the secretory pathway, suggesting a shared mechanism of channel regulation.(25-29) MMP-23’s catalytic domain displays structural homology with catalytic domains in other metalloproteases, and likely functions as an endopeptidase. MMP-23’s ShK domain lies immediately after the catalytic domain and is connected to the IgCAM domain by a short proline-rich linker. It shares phylogenetic relatedness to sea anemone toxins and ICR-CRISP domains, being most similar to the BgK toxin from sea anemone Bunodosoma granulifera.(25-29)  This ShK domain blocks voltage-gated potassium channels (KV1.6 > KV1.3 > KV1.1 = KV3.2 > Kv1.4, in decreasing potency) in the nanomolar to low micromolar range.(25) KV1.3 is required for sustaining calcium signaling during activation of human T cells.(46,57,58) By trapping KV1.3 in the endoplasmic reticulum via the prodomain, and by blocking the KV1.3 channel with the ShK domain, MMP-23 may serve as an immune checkpoint to reduce excessive T cell activation during an immune response. In support, increased expression of MMP-23 in melanoma cancer cells decreases tumor-infiltrating lymphocytes, and is associated with cancer recurrence and shorter periods of progression-free survival.(28) However, in melanomas, expression of MMP-23 does not correlate with Kv1.3 expression, suggesting that MMP-23’s deleterious effect in melanomas may not be connected with its Kv1.3 channel-modulating function.(28) MMP-23’s C-terminal IgCAM domain shares sequence similarity with IgCAM domains in proteins known to mediate protein-protein and protein-lipid interactions (e.g. CDON, human Brother of CDO, ROBO1-4, hemicentin, NCAM1 and NCAM2).(25-29) In summary, the four domains of MMP-23 may work synergistically to modulate immune responses in vivo.

9. The COBALT tree in Figure 4 is actually a "Sequence similarity tree." The tree does not show real evolutionary history (phylogenetics) but sequence similarity across proteins.

Response
We have replaced “COBALT tree” with “sequence similarity tree”.

REFERENCES

10. Citation #1 (the actual number) is used twice, with the first looks out of place and odd formatting.

Response
Changes have been made.

Editorial comments[edit]

Comments by Thomas Shafee
These comments were submitted on 2018-05-16, and refer to this previous version of the article

The article's references have been formatted the journal's format. In the submitted draft, there were a number of references that were not directly mentioned in-line. Please check if there are logical locations in the text to mention them. The references are listed by their original numbering belowː

  • 2. Harvey AL, Anderson AJ, Rowan EG, Marshall DL, Castañeda O and Karlsson E. Dendrotoxin-like activity isolated from sea anemones. Br. J. Pharmac. 1991;104:34P.
  • 6. Pennington MW, Mahnir VM, Krafte DS, Zaydenberg I, Byrnes ME, Khaytin I, Crowley K, Kem WR. Identification of three separate binding sites on ShK toxin, a potent inhibitor of voltage-dependent potassium channels in human T-lymphocytes and rat brain. Biochem Biophys Res Commun. 1996;219:696-701.
  • 8. Dauplais M, Lecoq A, Song J, Cotton J, Jamin N, Gilquin B, Roumestand C, Vita C, de Medeiros CL, Rowan EG, Harvey AL, Ménez A. On the convergent evolution of animal toxins. Conservation of a diad of functional residues in potassium channel-blocking toxins with unrelated structures. J Biol Chem. 1997;272:4302-4309.
  • 10. Tudor JE, Pennington MW, Norton RS. Ionisation behaviour and solution properties of the potassium-channel blocker ShK toxin. Eur J Biochem. 1998;251:133-141.
  • 12. Pennington MW, Lanigan MD, Kalman K, Mahnir VM, Rauer H, McVaugh CT, Behm D, Donaldson D, Chandy KG, Kem WR, Norton RS. Role of disulfide bonds in the structure and potassium channel blocking activity of ShK toxin. Biochemistry. 1999;38:14549-14558.
  • 13. Lanigan MD, Tudor JE, Pennington MW, Norton RS. A helical capping motif in ShK toxin and its role in helix stabilization. Biopolymers. 2001;58:422-436.
  • 16. Baell JB, Harvey AJ, Norton RS. Design and synthesis of type-III mimetics of ShK toxin. J Comput Aided Mol Des. 2002;16:245-62.
  • 21. Tsang SW, Nguyen CQ, Hall DH, Chow KL. mab-7 enspan style = "font-family: monospace;"s a novel transmembrane protein that orchestrates sensory ray morphogenesis in C. elegans. Dev Biol. 2007;312:353-366.
  • 33.  Chang SC, Galea CA, Leung EW, Tajhya RB, Beeton C, Pennington MW, Norton RS. Expression and isotopic labelling of the potassium channel blocker ShK toxin as a thioredoxin fusion protein in bacteria. Toxicon. 2012;60:840-850.
  • 35.  Dang B, Kubota T, Mandal K, Bezanilla F, Kent SB. Native chemical ligation at Asx-Cys, Glx-Cys: chemical synthesis and high-resolution X-ray structure of ShK toxin by racemic protein crystallography. J Am Chem Soc. 2013;135:11911-11919.
  • 37.  Lioudyno MI, Birch AM, Tanaka BS, Sokolov Y, Goldin AL, Chandy KG, Hall JE, Alkire MT. Shaker-related potassium channels in the central medial nucleus of the thalamus are important molecular targets for arousal suppression by volatile general anesthetics. J Neurosci. 2013;33:16310-16322.
  • 39.  Chhabra S, Chang SC, Nguyen HM, Huq R, Tanner MR, Londono LM, Estrada R, Dhawan V, Chauhan S, Upadhyay SK, Gindin M, Hotez PJ, Valenzuela JG, Mohanty B, Swarbrick JD, Wulff H, Iadonato SP, Gutman GA, Beeton C, Pennington MW, Norton RS, Chandy KG. Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: implications for autoimmune diseases. FASEB J. 2014;28:3952-3964.
  • 42.  Zhao R, Dai H, Mendelman N, Cuello LG, Chill JH, Goldstein SA. Designer and natural peptide toxin blockers of the KcsA potassium channel identified by phage display. Proc Natl Acad Sci U S A. 2015;112:E7013-E7021.
  • 78.  Tucker K, Overton JM, Fadool DA. Kv1.3 gene-targeted deletion alters longevity and reduces adiposity by increasing locomotion and metabolism in melanocortin-4 receptor-null mice. Int J Obes (Lond). 2008;32:1222-1232.


Refs 21 and 78 have been correctly integrated. The other references above were included in the inline citation "(2-46)". Since this number of citation to one sentence isn't compatible with out reference format, I have included them as a "further reading" section. T.Shafee(Evo﹠Evo)talk 04:13, 27 May 2018 (UTC)
Since these references are used in figure 1, the have been included as 'invisible references' (via <span style="font-size:0px">...</span>) in the main text. T.Shafee(Evo﹠Evo)talk 12:45, 5 June 2018 (UTC)

Additional author response[edit]

Response

Preprint - ShK toxin history, structure and therapeutic applications for autoimmune diseases - Author response.pdf

A


Author-annotated response pdf file.

We thank both the reviewers for their comments that have helped immensely in improving the manuscript. Please find below our responses to each of the reviewers’ comments.

Other changes: We have added 15 new references that are highlighted in blue. We have added 15 sentences in the text in the sections on ShK-related peptides in parasitic worms, T cell modulation, pristane-induced arthritis and atopic dermatitis; these are highlighted in blue.