Journal
SCIENCE
Volume 317, Issue 5844, Pages 1544-1548Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1142819
Keywords
-
Categories
Funding
- NIDDK NIH HHS [R01-DK622229] Funding Source: Medline
- NIGMS NIH HHS [R01 GM081592-02, F32-GM074398, R01 GM081592-01, R01-GM081592, R01 GM081592, F32 GM074398] Funding Source: Medline
Ask authors/readers for more resources
The structural mechanisms by which proteins have evolved new functions are known only indirectly. We report x-ray crystal structures of a resurrected ancestral protein-the similar to 450 million-year-old precursor of vertebrate glucocorticoid (GR) and mineralocorticoid (MR) receptors. Using structural, phylogenetic, and functional analysis, we identify the specific set of historical mutations that recapitulate the evolution of GR's hormone specificity from an MR-like ancestor. These substitutions repositioned crucial residues to create new receptor-ligand and intraprotein contacts. Strong epistatic interactions occur because one substitution changes the conformational position of another site. Permissive mutations-substitutions of no immediate consequence, which stabilize specific elements of the protein and allow it to tolerate subsequent function-switching changes-played a major role in determining GR's evolutionary trajectory.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available