PMID- 11075811
OWN - NLM
STAT- MEDLINE
DCOM- 20010531
LR  - 20131121
IS  - 0888-8809 (Print)
IS  - 0888-8809 (Linking)
VI  - 14
IP  - 11
DP  - 2000 Nov
TI  - Regulation of ligand-induced heterodimerization and coactivator interaction by 
      the activation function-2 domain of the vitamin D receptor.
PG  - 1776-87
AB  - Twenty-epi analogs of 1alpha,25-dihydroxyvitamin D3 (1,25D3) are 100-1000 times 
      more potent transcriptionally than the natural hormone. To determine whether this 
      enhanced activity is mediated through modulation of the dimerization process or 
      through interaction with coactivators, we performed quantitative protein-protein 
      interaction assays with in vitro translated vitamin D receptor (ivtVDR) and 
      fusion proteins containing glutathione-S-transferase (GST) and either the 
      ligand-binding domain of retinoid X receptor (RXRalpha), or the nuclear 
      receptor-interacting domain of the steroid receptor coactivator 1 (SRC-1), or the 
      glucocorticoid receptor-interacting protein 1 (GRIP-1). We found that 
      heterodimerization of the ligand-binding domains of RXRalpha and VDR was 
      primarily deltanoid dependent as was the interaction of VDR with the SRC-1 or 
      with GRIP-1. The ED50 for induction of heterodimerization was 2 nM for 1,25D3 and 
      0.05 nM for 20-epi-1,25D3. However, the ED50 for induction of VDR interaction 
      with SRC-1 was similar for both 1,25D3 and the 20-epi analog (ED50 = 0.7-1.0 nM) 
      as was the ED50 for ligand-mediated interaction of VDR with GRIP-1 (ED50 = 
      0.1-0.3 nM). Mutations in heptad 9 diminished both 1,25D3 and the 20-epi 
      analog-mediated dimerization, without changing binding of these ligands to VDR. 
      Mutations in VDR's activation function 2 (AF-2) domain/helix 12 residues 
      diminished the ability of 1,25D3 to induce heterodimerization and interaction 
      with SRC-1. These mutations did not change the ability of 20-epi-1,25D3 to induce 
      dimerization but did diminish its ability to induce interaction with SRC-1. We 
      hypothesize that both the hormone and the analog stabilize receptor conformations 
      that expose VDR's functional interfaces. The mechanisms by which the two ligands 
      expose these functional interfaces differ with respect to participation of the 
      AF-2 domain.
FAU - Liu, Y Y
AU  - Liu YY
AD  - Department of Medical Specialties, The University of Texas M. D. Anderson Cancer 
      Center, Houston 77030, USA.
FAU - Nguyen, C
AU  - Nguyen C
FAU - Peleg, S
AU  - Peleg S
LA  - eng
GR  - DK-50583/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Endocrinol
JT  - Molecular endocrinology (Baltimore, Md.)
JID - 8801431
RN  - 0 (Ligands)
RN  - 0 (Nuclear Receptor Coactivator 2)
RN  - 0 (Receptors, Calcitriol)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinoid X Receptors)
RN  - 0 (Transcription Factors)
RN  - EC 2.3.1.48 (Histone Acetyltransferases)
RN  - EC 2.3.1.48 (Nuclear Receptor Coactivator 1)
RN  - FXC9231JVH (Calcitriol)
SB  - IM
MH  - Animals
MH  - Binding Sites
MH  - COS Cells
MH  - Calcitriol/chemistry/metabolism/pharmacology
MH  - Dimerization
MH  - Histone Acetyltransferases
MH  - Ligands
MH  - Molecular Biology/methods
MH  - Mutation
MH  - Nuclear Receptor Coactivator 1
MH  - Nuclear Receptor Coactivator 2
MH  - Protein Structure, Tertiary
MH  - Receptors, Calcitriol/drug effects/genetics/*metabolism
MH  - Receptors, Retinoic Acid/genetics/*metabolism
MH  - Response Elements/drug effects/genetics
MH  - Retinoid X Receptors
MH  - Stereoisomerism
MH  - Structure-Activity Relationship
MH  - Transcription Factors/genetics/*metabolism
MH  - Transcription, Genetic
EDAT- 2000/11/15 11:00
MHDA- 2001/06/02 10:01
CRDT- 2000/11/15 11:00
PHST- 2000/11/15 11:00 [pubmed]
PHST- 2001/06/02 10:01 [medline]
PHST- 2000/11/15 11:00 [entrez]
AID - 10.1210/mend.14.11.0560 [doi]
PST - ppublish
SO  - Mol Endocrinol. 2000 Nov;14(11):1776-87. doi: 10.1210/mend.14.11.0560.