Crystal structure of an ancient protein: evolution by conformational epistasis.
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 approximately 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.
Ortlund
Eric A
EA
Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, USA.
Bridgham
Jamie T
JT
Redinbo
Matthew R
MR
Thornton
Joseph W
JW
D000450:Aldosterone / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D018360:Crystallography, X-Ray; D004843:Epistasis, Genetic; D019143:Evolution, Molecular; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D008024:Ligands; D016013:Likelihood Functions; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011965:Receptors, Glucocorticoid / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
D008024:Ligands; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D006854:Hydrocortisone
Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):57-62
15618400
Nature. 1995 Dec 14;378(6558):690-7
7501015
Science. 2006 Apr 7;312(5770):111-4
16601193
Evolution. 2000 Aug;54(4):1079-91
11005278
Nat Rev Genet. 2005 Feb;6(2):119-27
15716908
Nature. 1970 Feb 7;225(5232):563-4
5411867
Eur J Biochem. 1999 Feb;260(1):176-82
10091597
Nat Genet. 2004 Nov;36(11):1207-12
15502829
Curr Opin Struct Biol. 2002 Jun;12(3):400-8
12127461
Curr Opin Chem Biol. 2006 Oct;10(5):492-7
16935022
Curr Opin Chem Biol. 2006 Oct;10(5):498-508
16939713
Biol Chem. 1996 Jul-Aug;377(7-8):465-70
8922280
Evolution. 2002 Jul;56(7):1317-30
12206234
Nature. 2006 Dec 14;444(7121):929-32
17122770
Endocrinology. 2005 Jan;146(1):47-55
15486226
Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5869-74
16581913
Nat Rev Genet. 2004 May;5(5):366-75
15143319
J Biol Chem. 2005 Sep 2;280(35):31283-93
15967794
J Mol Biol. 2006 Sep 8;362(1):151-71
16916524
Science. 2005 Oct 21;310(5747):499-501
16239478
Evolution. 2005 Aug;59(8):1620-32
16329236
Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6483-8
16618920
Mol Biol Evol. 1998 Apr;15(4):355-69
9549087
Mol Biol Evol. 1983 Dec;1(1):1-28
6400645