The Glucocorticoid Receptor’s tau1c Activation Domain 35 Years on—Making Order out of Disorder

Round 1

Reviewer 1 Report

The authors gave a nice perspective on the history of discovery and evolutionary conservation of the human glucocorticoid receptor (hGR) protein, particularly as it relates to the tau1 domain of hGR. 

Consider revising the grammar in certain areas, such as lines 35,48-50, 116-120, 185-86, 222-223, and 232 where the same word is used in close proximity. In some instances replacing with a synonym is needed, and in others the second word seems redundant and can be removed. 

The heading "can proteins without structure mediate biological function?" should be numbered as section 4  and all subsequent sections should be  corrected to reflect this change. Also, this heading is the only one phrased as a question, consider revising for consistency. 

Lastly, consider rephrasing line 147 to 'isolated tau1c domain' for clarification as it is not a whole protein.

The writing is great overall, but as stated in notes to the authors there are a few areas where it could be improved. 

Author Response

Thank you for useful comments on the manuscript which have contributed to improved quality of the revised manuscript. The point by point replies to your comments (italics) are shown below.

The authors gave a nice perspective on the history of discovery and evolutionary conservation of the human glucocorticoid receptor (hGR) protein, particularly as it relates to the tau1 domain of hGR. 

Consider revising the grammar in certain areas, such as lines 35,48-50, 116-120, 185-86, 222-223, and 232 where the same word is used in close proximity. In some instances replacing with a synonym is needed, and in others the second word seems redundant and can be removed. 

Changes have been made along the lines suggested in each case and elsewhere.

The heading "can proteins without structure mediate biological function?" should be numbered as section 4  and all subsequent sections should be  corrected to reflect this change. Also, this heading is the only one phrased as a question, consider revising for consistency. 

Changes made in accordance with the comment.

Lastly, consider rephrasing line 147 to 'isolated tau1c domain' for clarification as it is not a whole protein.

Change made in accordance with the comment.

Reviewer 2 Report

The perspective article "The glucocorticoid receptor tau1c activation domain 35 years on - making order out of disorder" by Anthony Wright gives a historical perspective for discovery and characterization of N-terminal IDR domain of GR within context of recent findings in the field. The article is well written, constructed and enjoyable to read. The historical aspects of the findings and their modern interpretations are well chracterized through personal involvement and offer reader an interesting journey through the discovery and analysis process. Only part where I got paused and had to do a bit of research outside the article was the reanalysis/replotting of the experimental data in figure 1 and I would suggest that some clarification for this could be added before publishing. I have some suggestions that could help readers like myself to navigate through this figure a bit easier.
1) Mutations presented in figure have not been identified and are labeled according to wt amino acid. It could be beneficial for the reader to give couple of examples on how mutations change hydrophobicity: D196Y changes hydrophobicity from x to y - or- D196Y increases hydrophobicity by Z. This might help reader to understand that D and E mutations increase hydrophobicity because they have been changed to more hydrophobic amino acid (like Y), etc.

2) dotted lines in the figure represent the wt protein values - maybe it could be stated in the figure leged? For example the X-axis (Effect of mutations on activity in Log2-% of wild type) I had to check what log2(100) is to confirm this.

Author Response

Thank you for useful comments on the manuscript which have contributed to improved quality of the revised manuscript. The point by point replies to your comments (italics) are shown below.

The perspective article "The glucocorticoid receptor tau1c activation domain 35 years on - making order out of disorder" by Anthony Wright gives a historical perspective for discovery and characterization of N-terminal IDR domain of GR within context of recent findings in the field. The article is well written, constructed and enjoyable to read. The historical aspects of the findings and their modern interpretations are well chracterized through personal involvement and offer reader an interesting journey through the discovery and analysis process. Only part where I got paused and had to do a bit of research outside the article was the reanalysis/replotting of the experimental data in figure 1 and I would suggest that some clarification for this could be added before publishing. I have some suggestions that could help readers like myself to navigate through this figure a bit easier.
1) Mutations presented in figure have not been identified and are labeled according to wt amino acid. It could be beneficial for the reader to give couple of examples on how mutations change hydrophobicity: D196Y changes hydrophobicity from x to y - or- D196Y increases hydrophobicity by Z. This might help reader to understand that D and E mutations increase hydrophobicity because they have been changed to more hydrophobic amino acid (like Y), etc.

Changes made in accordance with the comment.

2) dotted lines in the figure represent the wt protein values - maybe it could be stated in the figure leged? For example the X-axis (Effect of mutations on activity in Log2-% of wild type) I had to check what log2(100) is to confirm this.

Change made in accordance with the comment.

Round 2

Reviewer 1 Report

I appreciate the author addressing my concerns and find the manuscript to be improved.