Oligomerization

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Oligomerization
Junping Chen
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Introduction Small lipophilic hormones,
such as steroid, thyroid hormones, retiniods and
vitamin D, are very important in generation,
growing and metabolism. These hormones induce
these functions by binding the nuclear receptors,
which bind to the DNA oligomerically as the
transcription factors. The receptors can also
bind to the activators or corepressors to
modulate DNA transcription.
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It has been reported that a remarkable
conservation in both the amino acid sequences and
different functional regions of nuclear
receptors.
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Figure 1. General design of transcription factors
in nuclear-receptor superfamily. The central
DNA-binding domain is homology among different
receptors. The C-terminal hormone-binding domain
exhibits less homology. The N-terminal regions
are various and may contain more activation
domains.
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The nuclear receptors have a N-terminal
region (A/B) of variable length (100500 amino
acids) as the transcription-activation domains.
The DNA-binding domain (DBD or region C) is near
the center and has the C4 zinc-finger motif. The
hormone-binding domain (region E) is near the
C-terminal end (region F).
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Figure 2. Schematic representation of
a nuclear receptor.
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oligomerization

• Monomer
• Homodimer
• Heterodimer

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Monomer

• Several orphan nuclear receptors can bind to DNA
  as monomers.
• The monomic HRE has a single AGG/TTCA following
  the 5-flanking A/T riched sequence.
• The receptors bind the HREs by the CTE whose
  third helix can contact the minor groove of DNA.
• The function of these receptors is still
  unknown.
• Example HNF4

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Figure 4. Binding sites for activators that
control transcription of the mouse transthyretin
(TTR) promoter in hepatocytes. HNF means
hepatocyte nuclear factor.
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Homodimer

• Homodimeric receptors are found both in the
  cytoplasm and nucleus.
• It suggests that their activity is regulated
  by controlling their transport from the cytoplasm
  to the nucleus.
• Eg hormone-dependent translocation of the
  homodimeric glucocorticoid receptor (GR)

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Figure 5. Model of hormone-dependent gene
activation by the glucocorticoid receptor (GR).
In the absence of hormone, GR is bound in a
complex with Hsp90 in the cytoplasm via its
ligand-binding domain (light purple). When
hormone is present, it binds to the GR
ligand-binding domain, causing a conformational
change in the ligand-binding domain that releases
the receptor from Hsp90. The receptor with bound
ligand is then translocated into the nucleus
where its DNA-binding domain (orange) binds to
response elements, allowing the activation domain
(green) to stimulate transcription of target
genes.
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• Steroid receptors almost always bind as homodimer
  to the HRE.
• The dimer interface in the LBD is the residues
  of helices 7,8,9 and the loop between helices
  8and 9.
• The dimer interface in the DBD which binds the
  palindromic DNA repeats with head to head
  arrangement involves the AAs of the D (linker
  between C and E regions) box.

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A
B
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Heterodimers

• Many non-steroidal hormone receptors, such as the
  receptors for all-trans retinoic acid, 9-cis
  retinoic acid, T3 and VD3 hormones, prefer
  heterodimers to binding the HREs of the genes. In
  these cases, the RXR (the receptor for 9-cis
  retinoic asid) is the most popular combining
  partner in the heterodimers.
• Some monomeric receptors can also form the
  heterodimers with RXR. Eg NGFI-B
• Some homodimeric receptors can also form
  heterodimers with RXR, such as, COUP-TF.

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(No Transcript)
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• There are two steps for heterodimers binding
  to DNA
• First, RXR bind its partner in solution by the
  LBDs.
• Second, DBDs bind to the DNA.

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• There are three types of heterodimeric
  complexes
• Unoccupied heterodimers
• Nonpermissive heterodimers can be activated
  only by the partners ligand. Eg, RXR/TR,
  RXR/VDR, and RXR/RAR
• Permissive heterodimers can be activated by the
  RXR ligands or the partner receptor ligands. Eg,
  PPAR/RXR, FXR/RXR, or NGFI-B/RXR

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(No Transcript)
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Interaction with other TFs
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Interaction With Coactivators

• Nuclear receptors have the AF-2 domain, which
  lies at the C-terminal and generates the
  hydropilic surface for coactivator binding.
• Coactivator families
• a. The p160 family SRC-1, SRC-2, p/CIP.
• b. PPARg coactivator-1
• c. RNA activator (SAR) works through the
  NH2-terminal AF-1 domain

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Figure 7. Domains of p160 families of receptor
coactivators. General features based on
sequencehomology. p160 coactivators has a basic
helix-loop-helix (bHLH) motif and a Per-Arnt-Sim
(PAS) homology region at the N-terminal. The
nuclear receptor interacting domain (RID)
contains three LXXLL motif. There are two
activation domains (AD1 and AD2) and an
intervening glutamine-rich (Q) region at the
C-terminal.
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Interaction with Corepressers

• NCoR or RIP-13
• SMRT (silent mediator for retinoic and thyroid
  hormone receptors)

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FIG. 8. Structure of the nuclear receptor
corepressors SMRT and NCoR. There are three
repressor domains (RD1, RD2, and RD3) and two
receptor interacting domains (RID). The RIDs
located at the C-terminal contain the extended
helical motif LXX I/H I XXX I/L.
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Reference

• Ana Aranda and Angel Pascual. Nuclear Hormone
  Receptors and Gene Expression. PHYSIOLOGICAL
  REVIEWS. 2001 July Vol. 81, No. 3 1270-95
• Lodish, Harvey Berk, Arnold Zipursky, S.
  Lawrence Matsudaira, Paul Baltimore, David
  Darnell, James E. Molecular Cell Biology. 4th ed.
  Chapter 10.7.
• Gerhard Krauss. Biochemistry of signal
  Transduction and Regulation. 2nd ed. Chapter 4.
  148-66.