Steep-Slope Gate-Connected Atomic Threshold Switching Field-Effect Transistor with MoS2 Channel and Its Application to Infrared Detectable Phototransistors.

For next-generation electronics and optoelectronics, 2D-layered nanomaterial-based field effect transistors (FETs) have garnered attention as promising candidates owing to their remarkable properties. However, their subthreshold swings (SS) cannot be lower than 60 mV/decade owing to the limitation of the thermionic carrier injection mechanism, and it remains a major challenge in 2D-layered nanomaterial-based transistors. Here, a gate-connected MoS2 atomic threshold switching FET using a nitrogen-doped HfO2-based threshold switching (TS) device is developed. The proposed device achieves an extremely low SS of 11 mV/decade and a high on-off ratio of ≈106 by maintaining a high on-state drive current due to the steep switching of the TS device at the gate region. In particular, the proposed device can function as an infrared detectable phototransistor with excellent optical properties. The proposed device is expected to pave the way for the development of future 2D channel-based electrical and optical transistors.

Infrared Detectable MoS2 Phototransistor and Its Application to Artificial Multilevel Optic-Neural Synapse.

Layered two-dimensional (2D) materials have entered the spotlight as promising channel materials for future optoelectronic devices owing to their excellent electrical and optoelectronic properties. However, their limited photodetection range caused by their wide bandgap remains a principal challenge in 2D layered materials-based phototransistors. Here, we developed a germanium (Ge)-gated MoS2 phototransistor that can detect light in the region from visible to infrared (λ = 520-1550 nm) using a detection mechanism based on band bending modulation. In addition, the Ge-gated MoS2 phototransistor is proposed as a multilevel optic-neural synaptic device, which performs both optical-sensing and synaptic functions on one device and is operated in different current ranges according to the light conditions: dark, visible, and infrared. This study is expected to contribute to the development of 2D material-based phototransistors and synaptic devices in next-generation optoelectronics.

Reduction of Threshold Voltage Hysteresis of MoS2 Transistors with 3-Aminopropyltriethoxysilane Passivation and Its Application for Improved Synaptic Behavior.

Although molybdenum disulfide (MoS2) is highlighted as a promising channel material, MoS2-based field-effect transistors (FETs) have a large threshold voltage hysteresis (Δ VTH) from interface traps at their gate interfaces. In this work, the Δ VTH of MoS2 FETs is significantly reduced by inserting a 3-aminopropyltriethoxysilane (APTES) passivation layer at the MoS2/SiO2 gate interface owing to passivation of the interface traps. The Δ VTH is reduced from 23 to 10.8 V by inserting the 1%-APTES passivation layers because APTES passivation prevents trapping and detrapping of electrons, which are the major source of the Δ VTH. The reduction in the density of interface traps ( Dit) is confirmed by the improvement of the subthreshold swing (SS) after inserting the APTES layer. Furthermore, the improvement in the synaptic characteristics of the MoS2 FET through the APTES passivation is investigated. Both inhibitory and excitatory postsynaptic currents (PSC) are increased by 33% owing to the reduction in the Δ VTH and the n-type doping effect of the APTES layer; moreover, the linearity of PSC characteristics is significantly improved because the reduction in Δ VTH enables the synaptic operation to be over the threshold region, which is linear. The application of the APTES gate passivation technique to MoS2 FETs is promising for reliable and accurate synaptic applications in neuromorphic computing technology as well as for the next-generation complementary logic applications.

Schottky Barrier Height Modulation Using Interface Characteristics of MoS2 Interlayer for Contact Structure.

Schottky barrier height (SBH) engineering of contact structures is a primary challenge to achieve high performance in nanoelectronic and optoelectronic applications. Although SBH can be lowered through various Fermi-level (FL) unpinning techniques, such as a metal/interlayer/semiconductor (MIS) structure, the room for contact metal adoption is too narrow because the work function of contact metals should be near the conduction band edge (CBE) of the semiconductor to achieve low SBH. Here, we propose a novel structure, the metal/transition metal dichalcogenide/semiconductor structure, as a contact structure that can effectively lower the SBH with wide room for contact metal adoption. A perpendicularly integrated molybdenum disulfide (MoS2) interlayer effectively alleviates FL pinning by reducing metal-induced gap states at the MoS2/semiconductor interface. Additionally, it can induce strong FL pinning of contact metals near its CBE at the metal/MoS2 interface. The technique using FL pinning and unpinning at metal/MoS2/semiconductor interfaces is first introduced in the MIS scheme to allow the use of various contact metals. Consequently, significant reductions of the SBH from 0.48 to 0.12 eV for GaAs and from 0.56 to 0.10 eV for Ge are achieved with several different contact metals. This work significantly reduces the dependence on contact metals with lowest SBH and proposes a new way of overcoming current severe contact issues for future nanoelectronic and optoelectronic applications.

Structural basis of the specific interaction of SMRT corepressor with histone deacetylase 4.

Modification of chromatin and related transcription factors by histone deacetylases (HDACs) is one of the major strategies for controlling gene expression in eukaryotes. The HDAC domains of class IIa HDACs repress the respective target genes by interacting with the C-terminal region of the silencing mediator for retinoid and thyroid receptor (SMRT) repression domain 3 (SRD3c). However, latent catalytic activity suggests that their roles as deacetylases in gene regulation are unclear. Here, we found that two conserved GSI-containing motifs of SRD3c are critical for HDAC4 binding. Two SMRT peptides including these motifs commonly form a ß-hairpin structure in the cleft and block the catalytic entry site of HDAC4. They interact mainly with class IIa HDAC-specific residues of HDAC4 in a closed conformation. Structure-guided mutagenesis confirmed critical interactions between the SMRT peptides and HDAC4 and -5 as well as the contribution of the Arg1369 residue in the first motif for optimal binding to the two HDACs. These results indicate that SMRT binding does not activate the cryptic deacetylase activity of HDAC4 and explain how class IIa HDACs and the SMRT-HDAC3 complex are coordinated during gene regulation.

OPTHiS Identifies the Molecular Basis of the Direct Interaction between CSL and SMRT Corepressor.

Notch signaling is an evolutionarily conserved pathway and involves in the regulation of various cellular and developmental processes. Ligand binding releases the intracellular domain of Notch receptor (NICD), which interacts with DNA-bound CSL [CBF1/Su(H)/Lag-1] to activate transcription of target genes. In the absence of NICD binding, CSL down-regulates target gene expression through the recruitment of various corepressor proteins including SMRT/NCoR (silencing mediator of retinoid and thyroid receptors/nuclear receptor corepressor), SHARP (SMRT/HDAC1-associated repressor protein), and KyoT2. Structural and functional studies revealed the molecular basis of these interactions, in which NICD coactivator and corepressor proteins competitively bind to ß-trefoil domain (BTD) of CSL using a conserved ϕWϕP motif (ϕ denotes any hydrophobic residues). To date, there are conflicting ideas regarding the molecular mechanism of SMRT-mediated repression of CSL as to whether CSL-SMRT interaction is direct or indirect (via the bridge factor SHARP). To solve this issue, we mapped the CSL-binding region of SMRT and employed a 'one- plus two-hybrid system' to obtain CSL interaction-defective mutants for this region. We identified the CSL-interaction module of SMRT (CIMS; amino acid 1816-1846) as the molecular determinant of its direct interaction with CSL. Notably, CIMS contains a canonical ϕWϕP sequence (APIWRP, amino acids 1832-1837) and directly interacts with CSL-BTD in a mode similar to other BTD-binding corepressors. Finally, we showed that CSL-interaction motif, rather than SHARP-interaction motif, of SMRT is involved in transcriptional repression of NICD in a cell-based assay. These results strongly suggest that SMRT participates in CSL-mediated repression via direct binding to CSL.

Novel Conductive Filament Metal-Interlayer-Semiconductor Contact Structure for Ultralow Contact Resistance Achievement.

In the post-Moore era, it is well-known that contact resistance has been a critical issue in determining the performance of complementary metal-oxide-semiconductor (CMOS) reaching physical limits. Conventional Ohmic contact techniques, however, have hindered rather than helped the development of CMOS technology reaching its limits of scaling. Here, a novel conductive filament metal-interlayer-semiconductor (CF-MIS) contact-which achieves ultralow contact resistance by generating CFs and lowering Schottky barrier height (SBH)-is investigated for potential applications in various nanodevices in lieu of conventional Ohmic contacts. This universal and innovative technique, CF-MIS contact, forming the CFs to provide a quantity of electron paths as well as tuning SBH of semiconductor is first introduced. The proposed CF-MIS contact achieves ultralow specific contact resistivity, exhibiting up to ∼×700 000 reduction compared to that of the conventional metal-semiconductor contact. This study proves the viability of CF-MIS contacts for future Ohmic contact schemes and that they can easily be extended to mainstream electronic nanodevices that suffer from significant contact resistance problems.

Postrecruitment Function of Yeast Med6 Protein during the Transcriptional Activation by Mediator Complex.

Med6 protein (Med6p) is a hallmark component of evolutionarily conserved Mediator complexes, and the genuine role of Med6p in Mediator functions remains elusive. For the functional analysis of Saccharomyces cerevisiae Med6p (scMed6p), we generated a series of scMed6p mutants harboring a small internal deletion. Genetic analysis of these mutants revealed that three regions (amino acids 33-42 (Δ2), 125-134 (Δ5), and 157-166 (Δ6)) of scMed6p are required for cell viability and are located at highly conserved regions of Med6 homologs. Notably, the Med6p-Δ2 mutant was barely detectable in whole-cell extracts and purified Mediator, suggesting a loss of Mediator association and concurrent rapid degradation. Consistent with this, the recombinant forms of Med6p having these mutations partially (Δ2) restore or fail (Δ5 and Δ6) to restore in vitro transcriptional defects caused by temperature-sensitive med6 mutation. In an artificial recruitment assay, Mediator containing a LexA-fused wild-type Med6p or Med6p-Δ5 was recruited to the lexA operator region with TBP and activated reporter gene expression. However, the recruitment of Mediator containing LexA-Med6p-Δ6 to lexA operator region resulted in neither TBP recruitment nor reporter gene expression. This result demonstrates a pivotal role of Med6p in the postrecruitment function of Mediator, which is essential for transcriptional activation by Mediator.

Schottky Barrier Height Engineering for Electrical Contacts of Multilayered MoS2 Transistors with Reduction of Metal-Induced Gap States.

The difficulty in Schottky barrier height (SBH) control arising from Fermi-level pinning (FLP) at electrical contacts is a bottleneck in designing high-performance nanoscale electronics and optoelectronics based on molybdenum disulfide (MoS2). For electrical contacts of multilayered MoS2, the Fermi level on the metal side is strongly pinned near the conduction-band edge of MoS2, which makes most MoS2-channel field-effect transistors (MoS2 FETs) exhibit n-type transfer characteristics regardless of their source/drain (S/D) contact metals. In this work, SBH engineering is conducted to control the SBH of electrical top contacts of multilayered MoS2 by introducing a metal-interlayer-semiconductor (MIS) structure which induces the Fermi-level unpinning by a reduction of metal-induced gap states (MIGS). An ultrathin titanium dioxide (TiO2) interlayer is inserted between the metal contact and the multilayered MoS2 to alleviate FLP and tune the SBH at the S/D contacts of multilayered MoS2 FETs. A significant alleviation of FLP is demonstrated as MIS structures with 1 nm thick TiO2 interlayers are introduced into the S/D contacts. Consequently, the pinning factor ( S) increases from 0.02 for metal-semiconductor (MS) contacts to 0.24 for MIS contacts, and the controllable SBH range is widened from 37 meV (50-87 meV) to 344 meV (107-451 meV). Furthermore, the Fermi-level unpinning effect is reinforced as the interlayer becomes thicker. This work widens the scope for modifying electrical characteristics of contacts by providing a platform to control the SBH through a simple process as well as understanding of the FLP at the electrical top contacts of multilayered MoS2.

Fermi-Level Unpinning Technique with Excellent Thermal Stability for n-Type Germanium.

A metal-interlayer-semiconductor (M-I-S) structure with excellent thermal stability and electrical performance for a nonalloyed contact scheme is developed, and considerations for designing thermally stable M-I-S structure are demonstrated on the basis of n-type germanium (Ge). A thermal annealing process makes M-I-S structures lose their Fermi-level unpinning and electron Schottky barrier height reduction effect in two mechanisms: (1) oxygen (O) diffusion from the interlayer to the contact metal due to high reactivity of a pure metal contact with O and (2) interdiffusion between the contact metal and semiconductor through grain boundaries of the interlayer. A pure metal contact such as titanium (Ti) provides very poor thermal stability due to its high reactivity with O. A structure with a tantalum nitride (TaN) metal contact and a titanium dioxide (TiO2) interlayer exhibits moderate thermal stability up to 400 °C because TaN has much lower reactivity with O than with Ti. However, the TiO2 interlayer cannot prevent the interdiffusion process because it is easily crystallized during thermal annealing and its grain boundaries act as diffusion path. A zinc oxide (ZnO) interlayer doped with group-III elements, such as an aluminum-doped ZnO (AZO) interlayer, acts as a good diffusion barrier due to its high crystallization temperature. A TaN/AZO/n-Ge structure provides excellent thermal stability above 500 °C as it can prevent both O diffusion and interdiffusion processes; hence, it exhibits Ohmic contact properties for all thermal annealing temperatures. This work shows that, to fabricate a thermally stable and low resistive M-I-S contact structure, the metal contact should have low reactivity with O and a low work-function, and the interlayer should have a high crystallization temperature and a low conduction band offset to Ge. Furthermore, new insights are provided for designing thermally stable M-I-S contact schemes for any semiconductor material that suffers from the Fermi-level pinning problem.

Effective Schottky Barrier Height Lowering of Metal/n-Ge with a TiO2/GeO2 Interlayer Stack.

A perfect ohmic contact formation technique for low-resistance source/drain (S/D) contact of germanium (Ge) n-channel metal-oxide-semiconductor field-effect transistors (MOSFETs) is developed. A metal-interlayer-semiconductor (M-I-S) structure with an ultrathin TiO2/GeO2 interlayer stack is introduced into the contact scheme to alleviate Fermi-level pinning (FLP), and reduce the electron Schottky barrier height (SBH). The TiO2 interlayer can alleviate FLP by preventing formation of metal-induced gap states (MIGS) with its very low tunneling resistance and series resistance and can provide very small electron energy barrier at the metal/TiO2 interface. The GeO2 layer can induce further alleviation of FLP by reducing interface state density (Dit) on Ge which is one of main causes of FLP. Moreover, the proposed TiO2/GeO2 stack can minimize interface dipole formation which induces the SBH increase. The M-I-S structure incorporating the TiO2/GeO2 interlayer stack achieves a perfect ohmic characteristic, which has proved unattainable with a single interlayer. FLP can be perfectly alleviated, and the SBH of the metal/n-Ge can be tremendously reduced. The proposed structure (Ti/TiO2/GeO2/n-Ge) exhibits 0.193 eV of effective electron SBH which achieves 0.36 eV of SBH reduction from that of the Ti/n-Ge structure. The proposed M-I-S structure can be suggested as a promising S/D contact technique for nanoscale Ge n-channel transistors to overcome the large electron SBH problem caused by severe FLP.

The Effect of Interfacial Dipoles on the Metal-Double Interlayers-Semiconductor Structure and Their Application in Contact Resistivity Reduction.

We demonstrate the contact resistance reduction for III-V semiconductor-based electrical and optical devices using the interfacial dipole effect of ultrathin double interlayers in a metal-interlayers-semiconductor (M-I-S) structure. An M-I-S structure blocks metal-induced gap states (MIGS) to a sufficient degree to alleviate Fermi level pinning caused by MIGS, resulting in contact resistance reduction. In addition, the ZnO/TiO2 interlayers of an M-I-S structure induce an interfacial dipole effect that produces Schottky barrier height (ΦB) reduction, which reduces the specific contact resistivity (ρc) of the metal/n-type III-V semiconductor contact. As a result, the Ti/ZnO(0.5 nm)/TiO2(0.5 nm)/n-GaAs metal-double interlayers-semiconductor (M-DI-S) structure achieved a ρc of 2.51 × 10-5 Ω·cm2, which exhibited an ∼42 000× reduction and an ∼40× reduction compared to the Ti/n-GaAs metal-semiconductor (M-S) contact and the Ti/TiO2(0.5 nm)/n-GaAs M-I-S structure, respectively. The interfacial dipole at the ZnO/TiO2 interface was determined to be approximately -0.104 eV, which induced a decrease in the effective work function of Ti and, therefore, reduced ΦB. X-ray photoelectron spectroscopy analysis of the M-DI-S structure also confirmed the existence of the interfacial dipole. On the basis of these results, the M-DI-S structure offers a promising nonalloyed Ohmic contact scheme for the development of III-V semiconductor-based applications.

Asymmetrically contacted germanium photodiode using a metal-interlayer-semiconductor-metal structure for extremely large dark current suppression.

In this study, we proposed germanium (Ge) metal-interlayer-semiconductor-metal (MISM) photodiodes (PD), with an anode of a metal-interlayer-semiconductor (MIS) contact and a cathode of a metal-semiconductor (MS) contact, to efficiently suppress the dark current of Ge PD. We selected titanium dioxide (TiO2) as an interlayer material for the MIS contact, due to its large valence band offset and negative conduction band offset to Ge. We significantly suppress the dark current of Ge PD by introducing the MISM structure with a TiO2 interlayer, as this enhances the hole Schottky barrier height, and thus acts as a large barrier for holes. In addition, it collects photo-generated carriers without degradation, due to its negative conduction band offset to Ge. This reduces the dark current of Ge MISM PDs by ×8000 for 7-nm-thick TiO2 interlayer, while its photo current is still comparable to that of Ge metal-semiconductor-metal (MSM) PDs. Furthermore, the proposed Ge PD shows ×6,600 improvement of the normalized photo-to-dark-current ratio (NPDR) at a wavelength of 1.55 µm. The proposed Ge MISM PD shows considerable promise for low power and high sensitivity Ge-based optoelectronic applications.

Mutagenesis Study Reveals the Rim of Catalytic Entry Site of HDAC4 and -5 as the Major Binding Surface of SMRT Corepressor.

Histone deacetylases (HDACs) play a pivotal role in eukaryotic gene expression by modulating the levels of acetylation of chromatin and related transcription factors. In contrast to class I HDACs (HDAC1, -2, -3 and -8), the class IIa HDACs (HDAC4, -5, -7 and -9) harbor cryptic deacetylases activity and recruit the SMRT-HDAC3 complex to repress target genes in vivo. In this regard, the specific interaction between the HDAC domain of class IIa HDACs and the C-terminal region of SMRT repression domain 3 (SRD3c) is known to be critical, but the molecular basis of this interaction has not yet been addressed. Here, we used an extensive mutant screening system, named the "partitioned one- plus two-hybrid system", to isolate SRD3c interaction-defective (SRID) mutants over the entire catalytic domains of HDAC4 (HDAC4c) and -5. The surface presentation of the SRID mutations on the HDAC4c structure revealed that most of the mutations were mapped to the rim surface of the catalytic entry site, strongly suggesting this mutational hot-spot region as the major binding surface of SRD3c. Notably, among the HDAC4c surface residues required for SRD3c binding, some residues (C667, C669, C751, D759, T760 and F871) are present only in class IIa HDACs, providing the molecular basis for the specific interactions between SRD3c and class IIa enzymes. To investigate the functional consequence of SRID mutation, the in vitro HDAC activities of HDAC4 mutants immuno-purified from HEK293 cells were measured. The levels of HDAC activity of the HDAC4c mutants were substantially decreased compared to wild-type. Consistent with this, SRID mutations of HDAC4c prevented the association of HDAC4c with the SMRT-HDAC3 complex in vivo. Our findings may provide structural insight into the binding interface of HDAC4 and -5 with SRD3c, as a novel target to design modulators specific to these enzymes.

Germanium p-i-n avalanche photodetector fabricated by point defect healing process.

In this Letter, we report Ge p-i-n avalanche photodetectors (APD) with low dark current (sub 1 µA below V(R)=5 V), low operating voltage (avalanche breakdown voltage=8-13 V), and high multiplication gain (440-680) by exploiting a point defect healing method (between 600°C and 650°C) and optimizing the doping concentration of the intrinsic region (p-type ~10¹7 cm⁻³). In addition, Raman spectroscopy and electrochemical capacitance voltage analyses were performed to investigate the junction interfaces in more detail. This successful demonstration of Ge p-i-n APD with low dark current, low operating voltage, and high gain is promising for low-power and high-sensitivity Ge PD applications.

Orphan nuclear receptor DAX-1 acts as a novel corepressor of liver X receptor alpha and inhibits hepatic lipogenesis.

DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene 1) is a member of the nuclear receptor superfamily that can repress diverse nuclear receptors and has a key role in adreno-gonadal development. Our previous report has demonstrated that DAX-1 can inhibit hepatocyte nuclear factor 4alpha transactivity and negatively regulate gluconeogenic gene expression (Nedumaran, B., Hong, S., Xie, Y. B., Kim, Y. H., Seo, W. Y., Lee, M. W., Lee, C. H., Koo, S. H., and Choi, H. S. (2009) J. Biol. Chem. 284, 27511-27523). Here, we further expand the role of DAX-1 in hepatic energy metabolism. Transfection assays have demonstrated that DAX-1 can inhibit the transcriptional activity of nuclear receptor liver X receptor alpha (LXRalpha). Physical interaction between DAX-1 and LXRalpha was confirmed Immunofluorescent staining in mouse liver shows that LXRalpha and DAX-1 are colocalized in the nucleus. Domain mapping analysis shows that the entire region of DAX-1 is involved in the interaction with the ligand binding domain region of LXRalpha. Competition analyses demonstrate that DAX-1 competes with the coactivator SRC-1 for repressing LXRalpha transactivity. Chromatin immunoprecipitation assay showed that endogenous DAX-1 recruitment on the SREBP-1c gene promoter was decreased in the presence of LXRalpha agonist. Overexpression of DAX-1 inhibits T7-induced LXRalpha target gene expression, whereas knockdown of endogenous DAX-1 significantly increases T7-induced LXRalpha target gene expression in HepG2 cells. Finally, overexpression of DAX-1 in mouse liver decreases T7-induced LXRalpha target gene expression, liver triglyceride level, and lipid accumulation. Overall, this study suggests that DAX-1, a novel corepressor of LXRalpha, functions as a negative regulator of lipogenic enzyme gene expression in liver.

The orphan nuclear receptor DAX-1 acts as a novel transcriptional corepressor of PPARgamma.

DAX-1 is an atypical nuclear receptor (NR) which functions primarily as a transcriptional corepressor of other NRs via heterodimerization. Peroxisome proliferator-activated receptor (PPAR) gamma is a ligand-dependent NR which performs a key function in adipogenesis. In this study, we evaluated a novel cross-talk mechanism between DAX-1 and PPARgamma. Transient transfection assays demonstrated that DAX-1 inhibits the transactivity of PPARgamma in a dose-dependent manner. DAX-1 directly competed with the PPARgamma coactivator (PGC)-1alpha for binding to PPARgamma. Endogenous levels of DAX-1 were significantly lower in differentiated 3T3-L1 adipocytes as compared to preadipocytes. Using a retroviral expression system, we demonstrated that DAX-1 overexpression downregulates the expression of PPARgamma target genes, resulting in an attenuation of adipogenesis in 3T3-L1 cells. Our results suggest that DAX-1 acts as a corepressor of PPARgamma and performs a potential function in the regulation of PPARgamma-mediated cellular differentiation.

Functional conservation of the glutamine-rich domains of yeast Gal11 and human SRC-1 in the transactivation of glucocorticoid receptor Tau 1 in Saccharomyces cerevisiae.

The yeast Gal11 protein, a component of the Mediator complex, is required for the transcriptional activation of many class II genes as a physiological target of various activator proteins in vivo. In this study, we identified the yeast (Saccharomyces cerevisiae) Mediator complex as a novel coactivator of the transcriptional activity of the glucocorticoid receptor (GR) tau 1 (tau1), the major transcriptional activation domain of the GR. GR tau1 directly interacted with the Mediator complex in vivo and in vitro in a Gal11 module-dependent manner, and the Gal11p subunit interacted directly with GR tau1. Specific amino acid residues within the glutamine-rich (Qr) domain of Gal11p (residues 116 to 277) were essential for its interaction with GR tau1 and GR tau1 transactivity in yeast, as demonstrated by mutational analysis of the Gal11 Qr domain, which is highly conserved among human steroid receptor coactivator (SRC) proteins. A Gal11p variant, mini-Gal11p, comprised of the Mediator association and Qr domains of Gal11p or chimeric mini-Gal11p containing the Qr domain of SRC-1 could potentiate the GR tau1 transactivity in a gal11Delta yeast strain. These results suggest that there is functional conservation between Qr domains of yeast Gal11p and mammalian SRC proteins as direct targets of activator proteins in yeast.

RXR heterodimerization allosterically activates LXR binding to the second NR box of activating signal co-integrator-2.

ASC-2 (activating signal co-integrator-2) is a transcriptional co-activator that mediates the transactivation of NRs (nuclear receptors) via direct interactions with these receptors. ASC-2 contains two separate NR-interaction domains harbouring a core signature motif, LXXLL (where X is any amino acid), named the NR box. Although the first NR box (NR box-1) of ASC-2 interacts with many different NRs, the second NR box (NR box-2) specifically interacts with only LXR (liver X receptor), whose transactivation in vivo requires heterodimerization with RXR (retinoid X receptor). Interestingly, RXR has been shown to enhance the LXR transactivation, even in the absence of LXR ligand via a unique mechanism of allosteric regulation. In the present study we demonstrate that LXR binding to an ASC-2 fragment containing NR box-2 (Co4aN) is enhanced by RXR and even further by liganded RXR. We also identified specific residues in Co4aN involved in its interaction with LXR that were also required for the ASC-2-mediated transactivation of LXR in mammalian cells. Using these mutants, we found that the Co4aN-LXR interaction surface is not altered by the presence of RXR and RXR ligand and that the Ser(1490) residue is the critical determinant for the LXR-specific interaction of Co4aN. Notably the NR box-2, but not the NR box-1, is essential for ASC-2-mediated transactivation of LXR in vivo and for the interaction between LXR-RXR and ASC-2 in vitro. These results indicate that RXR does not interact directly with NR box-1 of ASC-2, but functions as an allosteric activator of LXR binding to NR box-2 of ASC-2.