The Inherent Coupling of Intrinsically Disordered Regions in the Multidomain Receptor Tyrosine Kinase KIT
Round 1
Reviewer 1 Report
The authors report an exhaustive analysis of molecular dinamics simulations of the cytosolic part of the receptor tyrosine kinase KIT. They identify interdependence of movement of distal, disordered regions of the protein, which points toward allosteric communication between these regions. Altogether, the manuscript is fine, albeit a bit long and it is technically sound. My two points of criticism that the authors should take into account are:
- KIT is introduced relatively late in the Introduction (lines 82-89), whereas prior text refers to RTKs in general. However, in this initial part, Figure 1 is references, which shows the structure of KIT. Hence, the reader is presented with a structure of this specific RTK before he is properly introduced to it. It would be better if KIT were introduced earlier in the Introduction (before Figure 1 is referenced).
- There are some grammatical and typografic errors in the manuscript. I suggest a thorough proofreading.
Author Response
Reviewer 1
The authors report an exhaustive analysis of molecular dinamics simulations of the cytosolic part of the receptor tyrosine kinase KIT. They identify interdependence of movement of distal, disordered regions of the protein, which points toward allosteric communication between these regions. Altogether, the manuscript is fine, albeit a bit long and it is technically sound. My two points of criticism that the authors should take into account are:
- KIT is introduced relatively late in the Introduction (lines 82-89), whereas prior text refers to RTKs in general. However, in this initial part, Figure 1 is references, which shows the structure of KIT. Hence, the reader is presented with a structure of this specific RTK before he is properly introduced to it. It would be better if KIT were introduced earlier in the Introduction (before Figure 1 is referenced).
- There are some grammatical and typografic errors in the manuscript. I suggest a thorough proofreading.
Response: The Authors thank Reviewer 1 for very positive comments of the manuscript and critical remarks which were considered in the revised version of the manuscript. In particular, Figure 1 was cited as an example of the RTK structural organisation (see the legend), and the spelling was corrected.
Reviewer 2 Report
Dear authors,
you can find my report in the attached file.
Comments for author File: 
Comments.pdf
Author Response
Reviewer 2
Report for the Authors The Article entitled “The Inherent Coupling of Intrinsically Disordered Regions in the Multidomain Receptor Tyrosine Kinase KIT”, submitted by Ledoux J. et al., reports the investigation on the role of the KIT cytoplasmic domain in triggering several signaling cascades. In particular, authors propose a 3D model to describe KIT intrinsic and extrinsic functionality, suggesting that all properties of KIT in the active status depend on events happening in the inactive status. In my opinion, this is a complete and well done study. However, if discussion, methods and data analysis clearly describe the project, results are confusing in some parts, and should be revised in the explanation. Lastly, I recommend English revision and editing.
Response: The Authors thank Reviewer 2 for positive comments of the manuscript and critical remarks which were considered in the revised version of the manuscript. Our responses are supplied after each minor concern.
Minor Revisions
Line 8: Please, modify “cytoplasmic (CD) domain” in “cytoplasmic domain (CD)”.
Response: Position of (CD) was modified
Line 44: Remove … and indicate in brackets all the diversified units or add a proper reference.
Response: References was added
Line 90: Why you use italics for “composed”?
Response: Italic was changed for regular characters
Line 97: Please modify “found” with a proper verbal time.
Response: It was changed for ‘detected’
Lines 248-251: Clarify this part.
Taking into account the complex multi-segment structure of the elongated JMR, its characterization was carried out in two steps: first, its position relative to the TK domain was estimated very roughly, as a distance between two centroids, one of them is determined on TKD and the other on all JMR atoms. In the second step, we performed a more detailed characterization of the JMR position by considering each segment. To do this, the distances between the TKD centroid and the centroid of each segment were calculated to represent the positions of the different JMR segments with respect to the common point - the TKD centroid.
Line 253: Please modify “positions” in “position”.
Response: It was changed.
Lines 283: Remove underscore.
Underscore was removed.
Lines 314-316: Please use italics only for the β letter.
Response: Italic was changed for regular style.
Line 438: Remove ellipsis.
Ellipsis at this line was not localised.
Lines 489-490: Please delete the repeated sentence “Each FEL shows … multidomain KIT”, already reported above.
Response: The repeated sentence was removed.
Line 509: Please correct “PC components” in “PCA components” as indicated in line 486.
Response: It was corrected.
Line 725: Fifteen or 50 modes?
Response: The number of modes was precised: 15 modes.
Line 817: Modify “con-formation” in “conformation”.
Response: The hyphen was removed
Lines 146, 551, 851, 863, 865: Please, report references in the proper manner.
Response: The references were reported in the proper manner.
Line 120, 244, 540: Remove comma in inappropriate sites.
Response: It was done.
