PMID- 10648597
OWN - NLM
STAT- MEDLINE
DCOM- 20000215
LR  - 20190508
IS  - 0270-7306 (Print)
IS  - 0270-7306 (Linking)
VI  - 20
IP  - 4
DP  - 2000 Feb
TI  - The orphan nuclear receptor SHP utilizes conserved LXXLL-related motifs for
      interactions with ligand-activated estrogen receptors.
PG  - 1124-33
AB  - SHP (short heterodimer partner) is an unusual orphan nuclear receptor consisting 
      only of a ligand-binding domain, and it exhibits unique features of interaction
      with conventional nuclear receptors. While the mechanistic basis of these
      interactions has remained enigmatic, SHP has been suggested to inhibit nuclear
      receptor activation by at least three alternatives; inhibition of DNA binding via
      dimerization, direct antagonism of coactivator function via competition, and
      possibly transrepression via recruitment of putative corepressors. We now show
      that SHP binds directly to estrogen receptors via LXXLL-related motifs. Similar
      motifs, referred to as NR (nuclear receptor) boxes, are usually critical for the 
      binding of coactivators to the ligand-regulated activation domain AF-2 within
      nuclear receptors. In concordance with the NR box dependency, SHP requires the
      intact AF-2 domain of agonist-bound estrogen receptors for interaction. Mutations
      within the ligand-binding domain helix 12, or binding of antagonistic ligands,
      which are known to result in an incomplete AF-2 surface, abolish interactions
      with SHP. Supporting the idea that SHP directly antagonizes receptor activation
      via AF-2 binding, we demonstrate that SHP variants, carrying either
      interaction-defective NR box mutations or a deletion of the repressor domain,
      have lost the capacity to inhibit agonist-dependent transcriptional estrogen
      receptor activation. Furthermore, our studies indicate that SHP may function as a
      cofactor via the formation of ternary complexes with dimeric receptors on DNA.
      These novel insights provide a mechanistic explanation for the inhibitory role of
      SHP in nuclear receptor signaling, and they may explain how SHP functions as a
      negative coregulator or corepressor for ligand-activated receptors, a novel and
      unique function for an orphan nuclear receptor.
FAU - Johansson, L
AU  - Johansson L
AD  - Department of Biosciences at Novum, Karolinska Institute, Sweden.
FAU - Bavner, A
AU  - Bavner A
FAU - Thomsen, J S
AU  - Thomsen JS
FAU - Farnegardh, M
AU  - Farnegardh M
FAU - Gustafsson, J A
AU  - Gustafsson JA
FAU - Treuter, E
AU  - Treuter E
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Estrogen Receptor alpha)
RN  - 0 (Estrogen Receptor beta)
RN  - 0 (Ligands)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (Receptors, Estrogen)
RN  - 0 (nuclear receptor subfamily 0, group B, member 2)
SB  - IM
MH  - Amino Acid Motifs
MH  - Amino Acid Sequence
MH  - Animals
MH  - Binding Sites
MH  - Cell Line
MH  - Conserved Sequence
MH  - Dimerization
MH  - Estrogen Receptor alpha
MH  - Estrogen Receptor beta
MH  - Humans
MH  - Ligands
MH  - Molecular Sequence Data
MH  - Mutation
MH  - Protein Structure, Quaternary
MH  - Rats
MH  - Receptors, Cytoplasmic and Nuclear/*chemistry/genetics/*metabolism
MH  - Receptors, Estrogen/chemistry/genetics/*metabolism
MH  - Sequence Homology, Amino Acid
PMC - PMC85230
EDAT- 2000/01/29 09:00
MHDA- 2000/02/19 09:00
CRDT- 2000/01/29 09:00
PHST- 2000/01/29 09:00 [pubmed]
PHST- 2000/02/19 09:00 [medline]
PHST- 2000/01/29 09:00 [entrez]
AID - 10.1128/mcb.20.4.1124-1133.2000 [doi]
PST - ppublish
SO  - Mol Cell Biol. 2000 Feb;20(4):1124-33. doi: 10.1128/mcb.20.4.1124-1133.2000.