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Our lab’s newest paper published in PLoS One

I’m excited to announce that our latest paper has been published in PLoS One.  OK, this news is a little old since the paper came out March 29th, but with the end of the academic year, a trip to the ARVO eye meetings in Florida and the start of summer research with three undergraduate students in lab it has taken me some time to write this post.

Antarctic toothfish alpha A crystallin has evolved more flexibility to function at low temperatures

My lab studies the function of a family of small heat shock proteins called alpha crystallins, which plays a role in keeping the lens of the eye transparent and focusing light on the retina.  These proteins are also found in other tissues like brain and muscle where they protect cells during physiological stress.  Alpha crystallins keep other proteins from sticking to each other during this stress, which could otherwise cause a wide range of diseases such as Alzheimer’s and Parkinson’s.  Recent research also shows that more alpha crystallin is made during many types of cancer, perhaps as a protective response by cells.  We would like to better understand how alpha crystallins, and small heat shock proteins in general, protect other proteins and prevent disease.  Understanding this function might allow us to design altered alpha crystallins with greater protective abilities.  Our approach to studying alpha crystallin function is a bit unique as we examine these proteins in fishes.  Why fishes?  We use them as a model to dissect how natural selection has altered these proteins to function in different environmental settings.  In particular, we looked at alpha crystallin function in fish species with different body temperatures to see how evolution has molded this protein to protect other proteins in bodies as different as the Antarctic toothfish (-2 degrees C) and the zebrafish (27 degrees C).  This type of study is not possible in mammalian models like mice and rabbits whose body temperatures are all similar.

Structure of alpha A crystallin showing position of three amino acids that affect protective function

We hypothesized that the protective abilities of alpha A-crystallin, one of three alpha crystallins found in fishes, had evolved to function at the specific body temperature of the six fishes in our study.  We found just that.  When all six fish alpha A-crystallins were compared side by side at the same temperature, those from the cooler bodied fishes (like the Antarctic toothfish) were more flexible to compensate for the stabilizing effects of cold temperature.  This greater flexibility allowed them to protect other proteins more readily than the comparatively stiffer alpha crystallins from the warmer species.  By comparing the structure of all six proteins we identified three amino acid building blocks that differed between the cold and warm fishes that could cause this increase in protective function.

The most exciting part of our study was that when we took a zebrafish alpha A-crystallin and genetically engineered it to look like the Antarctic toothfish at the three amino acids, two of the changes increased its protective function.  By comparing alpha crystallins from these six fish species we were able to identify specific parts of the protein that may be evolving to fine-tune protective ability to different body temperatures, and then showed experimentally that those changes are functionally significant.  Because alpha A-crystallin is so well conserved between fishes and mammals we now want to see if similar changes will increase protection in the human version of this protein.  While it may seem unusual to study a protein that causes human disease in a bunch of fish, our new study shows that this comparative approach can be quite effective.  Stay tuned for updates.

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