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Journal Club: Tracking a complete voltage-sensor cycle with metal-ion bridges

In this post I would like to start an online discussion about a very interesting recent PNAS paper: Tracking a complete voltage-sensor cycle with metal-ion bridges by Henrion et al. I know that other people in the voltage-gated cation channel field are very interested in this paper and it also relates to many of the topics I have been discussing in my posts. I thought it would be a good idea to discuss it and a journal club type format encourages contributions from anyone who is interested. So read the paper and join in the discussion!

This paper, from the labs of Fredrick Elinder in Linköping University Sweden and Erik Lindahl in Stockholm University Sweden, defines 20 new interactions in the different conformations of the voltage-sensor domain (VSD) of the Shaker Kv channel. They measure these interactions by metal binding and stabilization of the different conformations in mutated channels. Using these newly defined interactions as constraints Henrion et al. then build Rosetta models of the different interactions using the open structure of the Kv1.2-2.1 paddle chimera (learn more about Rosetta at the Rosetta Commons website).

You can download the PDBs for these models here. The models represent five different possible conformations of the Shaker Kv channel (O, C1, C2, C3 and C4). Fig.1 one is a cartoon schematic of these five conformations (adapted from my post on the omega current).

Figure 1. Cartoons showing the different putative conformations of the Shaker Kv VSD. The sequence of the S4 transmembrane helix is shown at the top. The S4 arginines are color coded as in the cartoons. The model designations for the different conformations are show below each cartoon.

This is a very complex paper with lots of data and conclusions. It will take lots of effort to analyze and critique in detail, so this discussion will probably last a while. I will briefly write about what I think and why but I am very interested in finding out what other people think as well. If you want me to expand on anything just join in the conversation. Please contribute your thoughts to the discussion.

How this discussion will work

I will start by going figure by figure through the paper and the supplementary. There is a lot of data so this will take some time. If you want to skip ahead and start a discussion about any aspect of the paper, including the figures or the models please feel free.

Start a discussion about the paper by posting comments on this page (below). If you want to add to the discussion look over the comments below and:

1) If there is already a thread related to your question or comment reply to that thread, or

2) If there isn’t a thread related to your question or comment start a new thread by posting a comment.

The way this blog works is that I will have to approve each reply and comment before they are posted online. Therefore, there may be some delay between when you submit and when your comment appears.

As time goes on I might add to the main text of this post as well.

Rules

No haters. I will not post anything that is overly negative or rude.

Of course, critical analysis is encouraged (this is science after all). If you think there is something wrong with the paper, please let us know. However, why you think something is wrong in the paper is more important and interesting.

Also it is also ok to say you are skeptical about certain findings in the paper but, again, why you’re skeptical is the interesting part.

If you are impressed by, or find a conclusion particularly interesting please share your thoughts.

Conclusions from the discussion thus far…

  1. Really impressive amount of work by the authors. The number of mutants generated and characterized is staggering.
  2. The rough affinity of each Cd2+ interaction should have been reported in order to better judge the possibility of introduced structural distortions
  3. Underlying assumptions in the paper should have been discussed more clearly. For example, that S3b doesn’t move and how they sorted the different bridging interactions into the conformational states.

More to come…

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