Nucleic Acids Research, Vol 24, Issue 22 4513-4518, Copyright © 1996 by Oxford University Press
S Nayeri, JP Kahlen and C Carlberg
The nuclear receptor for 1,25-dihydroxyvitamin D3 (VD), VDR, is a
transcription factor that mediates all genomic actions of the hormone. The
activation of VDR by ligand induces a conformational change within its
ligand binding domain (LBD). Due to the lack of a crystal structure
analysis, biochemical methods have to be applied in order to investigate
the details of this receptor-ligand interaction. The limited protease
digestion assay can be used as a tool for the determination of a functional
dissociation constant (K(df)) of VDR with any potential ligand. This method
provided with the natural hormone VD two protease-resistant fragments of
the VDR LBD and with the 20-epi conformation of VD, known as MC1288, even
an additional fragment of intermediate size. These fragments were
interpreted as different receptor conformations and their decreasing size
was found to be associated with decreasing ligand binding affinity. A
critical amino acid for VDR's high ligand binding conformation has been
identified by C-terminal receptor truncations and point mutations as
phenylalanine 422. This amino acid appears to directly contact the ligand
and belongs to the ligand-inducible activation function-2 (AF-2) domain.
Moreover, functional assays supported the observation that high affinity
ligand binding is directly linked to transactivation function.
ARTICLES
The high affinity ligand binding conformation of the nuclear 1,25- dihydroxyvitamin D3 receptor is functionally linked to the transactivation domain 2 (AF-2)
Clinique de Dermatologie, Hopital Cantonal Universitaire, Geneve, Switzerland.
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