Together, the results revealed that every GARS mutation studied causes a structural opening in the resulting mutant protein. By superimposing the information obtained from the structures in solution to the high-resolution X-ray crystal structure of the wild-type GlyRS protein, Yang, He, Zhang and colleagues were able to determine that the structural opening maps to a common region of the GlyRS protein in all the mutants.
By becoming more open to potential new partners, the GlyRS mutants may gain a new function that is toxic to nerve cells. That would explain why CMT type 2D is inherited in a dominant fashion.
The team is now looking for proteins that might bind to this region and already have leads on several candidates. As exciting as this work is, says He, "this paper is just the start of the story; we have more story coming, and it's getting more and more exciting."
This disease mechanism may also apply to other conditions. "Some proteins may be relatively unstable and can be easily triggered into another conformation by different types of mutations," explained Yang. "This example deals with the GlyRS protein, but the general idea can be applied to many other mutation-induced human diseases."
One example may be ALS. Some inherited forms of ALS are caused in a gene that encodes the enzyme copper-zinc superoxide dismutase (commonly called SOD1). To da
|Contact: Mika Ono|
Scripps Research Institute