Evolution of Minimal Specificity and Promiscuity in Steroid Hormone Receptors 英文参考文献.docVIP

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Evolution of Minimal Specificity and Promiscuity in Steroid Hormone Receptors 英文参考文献.doc

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Evolution of Minimal Specificity and Promiscuity in Steroid Hormone Receptors 英文参考文献

EvolutionofMinimalSpecificityandPromiscuityin SteroidHormoneReceptors GeetaN.Eick1,2,JenniferK.Colucci3,MichaelJ.Harms1,EricA.Ortlund3,JosephW.Thornton1,2,4* 1InstituteofEcologyandEvolution,UniversityofOregon,Eugene,Oregon,UnitedStatesofAmerica,2HowardHughesMedicalInstitute,Eugene,Oregon,UnitedStates of America, 3Biochemistry Department, Emory University School of Medicine, Atlanta, Georgia, United States of America, 4Department of Human Genetics and DepartmentofEcologyandEvolution,UniversityofChicago,Chicago,Illinois,UnitedStatesofAmerica Abstract Mostproteinsareregulatedbyphysicalinteractionswithothermolecules;somearehighlyspecific,butothersinteractwith many partners. Despite much speculation, we know little about how and why specificity/promiscuity evolves in natural proteins.Itiswidelyassumedthatspecificproteinsevolvedfrommorepromiscuousancientformsandthatmostproteins’ specificity has been tuned to an optimal state by selection. Here we use ancestral protein reconstruction to trace the evolutionary history of ligand recognition in the steroid hormone receptors (SRs), afamily of hormone-regulated animal transcriptionfactors.WeresurrectedthedeepestancestralproteinsintheSRfamilyandcharacterizedthestructure-activity relationshipsbywhichtheydistinguishedamongligands.WefoundthatthatthemostancientsplitinSRevolutioninvolved a discrete switch from an ancient receptor for aromatized estrogens—including xenobiotics—to a derived receptor that recognizednon-aromatizedprogestagensandcorticosteroids.Thefamily’shistory,viewedinrelationtotheevolutionof their ligands, suggests that SRs evolved according to a principle of minimal specificity: at each point in time, receptors evolvedligandrecognitioncriteriathatwerejustspecificenoughtoparsethesetofendogenoussubstancestowhichthey were exposed. By studying the atomic structures of resurrected SR proteins, we found that their promiscuity evolved becausetheancestralbindingcavitywaslargerthantheprimaryligandandcontainedexcesshydrogenb