The Molecular History of Eukaryotic Life  Nuclear Receptors 


David Nelson  Dec. 13, 2000

	Nuclear receptors were called the largest family of transcription factors in a 
1994 Annual Rev. of Biochem. article (vol. 63, p. 453).  In a Nov. 98 article, more than 
300 sequences were known (PNAS 95, 13442-13447). These are internal receptors in contrast 
to the membrane receptors we just discussed.  The ligands for these receptors are 
hydrophobic and diffuse through the membranes of cells without specific transport 
proteins to bring them in.  They include steroids, retinoids, vitamin D and thyroid 
hormone. Vincent Laudet has been active in the study of the evolution of these receptors.  
His group has searched for the presence of nuclear receptors in many types of animals, 
plants and lower eukaryotes.  The approach was an exhastive PCR study using highly 
conserved regions of the nuclear receptors to make degenerate PCR primers that could be 
used to detect almost any member of the group.  The result was that nuclear receptors are 
strictly metazoan (animal).  They were not found in plants, algae, fungi or protists.  
Among animal species, they were not found in sponges, but they were present in Cnidarians 
(radial animals like jellyfish, hydras and corals) and all other more advanced animals.  
There are 270 nuclear hormone receptors in C. elegans alone.

	Many nuclear receptors do not have ligands identified.  These are called orphan 
receptors.  One surprising finding in this exhaustive search for receptors was that a 
given ligand did not appear in only one branch of the tree of receptors.  
Also, the receptors with known ligands were only found in recent subfamilies.  The 
authors concluded that the ability to bind ligand has only evolved recently and the 
ancestral nuclear receptors were probably orphan receptors.  This also suggests that many 
orphan receptors do not have any ligand that binds to them.  To function without ligand 
the receptor is proposed to have two conformations.  One binds to DNA and regulates gene 
function.  The other does not bind DNA.  The equilibrium between the two states 
determines how much time the gene is turned on.  Binding a ligand shifts the equilibrium 
to the DNA binding conformation.  Of course other things could shift this equilibrium 
too, like phosphorylation, temperature, etc.  This idea is new and will have to be 
debated and tested.  In 1999 a nomenclature system was adopted for nuclear receptors
(A unified nomenclature system for the nuclear receptor superfamily. Cell. 1999 Apr 
16;97(2):161-3).  Nomenclature is a serious problem as more genomes are sequenced and it 
needs to be addressed for most large families of genes.  

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