Thursday, May 2, 2013

Stephan does it again at Nature Communications

This week yet another paper at the nascent e-journal Nature Communications emerges from the publishing machine that is Dr. Stephan Pless.  This was our longest running and most difficult project to date and seeing it come out in such a great journal is fantastic.  I'll let folks read the paper to see what its all about but the summary is that the data (actual and theoretical) support the existence of a repulsive interaction between a co-evolved glutamate and phenylalanine side-chain that serves to 'fine-tune' channel gating by mildly destabilizing the open state of the channel.  There are most likely (many) other (unidentified) players in this crowded region of the channel, including lipids (and their polar head groups), maybe even PIP molecule or two, and the interaction as we describe it requires that the Phe aside chain is more or less fixed and facing the carboxylate of the glutamate side-chain.  But even with all of those qualifiers aside, its a pretty interesting possibility and might be important for the potassium channel's big brother, the sodium channel, where mutations at these sites can lead to inherited arrhythmia and painful syndromes.

This was the first project that Stephan and I decided to tackle in the newly founded lab way back in 2008.  The idea was simple: lets look at the energetic basis for why a group of aromatic phenylalanine and tyrosine residues that cluster around the inner opening of the channel are so important for potassium channel function.  I mean, if you do even modest mutations at any of these sites one ends up with functionally dead or a seriously messed up channel, so these residues must be doing something important, right?  We had just begun setting up the in vivo nonsense suppression in the lab (no small feat itself) and we had a full toolbox of nonnatural derivatives of  it seemed it would an easy way to quickly get a paper out for the lab and for Stephan's postdoc.  How wrong we were.  Almost 100 mutations (thanks, Ana!!), more than a few mix-ups (and emotional ups and downs), and 4+ years later, its out.  Lets just say it was an extended labor to birth this beast, and anesthetic was often required.  We owe a huge debt to our collaborator and friend Harley Kurata and his math wiz undergrad, John-Jose (aka J^2) Nunez for their help with the kinetic schemes and their work on the SCA analysis, which both served to push the story over the top.  Jason played a key chemical role as always with his input and timely turn-around on the synthesis requests.  Working with such great people makes our science better.  period.

See it here.

Congrats all around....and now onto the next one.........

No comments:

Post a Comment