Starting at 512Mb 6Gb/s/pin 1, GDDR5's speed and density have been steadily developing for about 10 years; recently achieving 8Gb 9Gb/s/pin 2 with per-pin timing training. Although 8Gb GDDR5X can ...operate at 12Gb/s 3 by increasing the burst length (BL) from 8 to 16, a degradation in system performance at a data granularity of 64B is seen. The I/O specification, using PLL clocking that additionally causes PLL jitter, has not changed much compared with GDDR5. To overcome these issues, GDDR6 introduced a dual channel for a data granularity of 32B with a BL16, per-bit training of l/ REF , and an equalizer with PLL-less clocking. This paper presents a 16Gb 18Gb/s/pin GDDR6 DRAM with a die architecture and high-speed circuit techniques on 1.35V DRAM process.
Ca
regulates several cellular functions, including signaling events, energy production, and cell survival. These cellular processes are mediated by Ca
-binding proteins, such as EF-hand superfamily ...proteins. Among the EF-hand superfamily proteins, allograft inflammatory factor-1 (AIF-1) and swiprosin-1/EF-hand domain-containing protein 2 (EFhd2) are cytosolic actin-binding proteins. AIF-1 modulates the cytoskeleton and increases the migration of immune cells. EFhd2 is also a cytoskeletal protein implicated in immune cell activation and brain cell functions. EFhd1, a mitochondrial fraternal twin of EFhd2, mediates neuronal and pro-/pre-B cell differentiation and mitoflash activation. Although EFhd1 is important for maintaining mitochondrial morphology and energy synthesis, its mechanism of action remains unclear. Here, we report the crystal structure of the EFhd1 core domain comprising a C-terminus of a proline-rich region, two EF-hand domains, and a ligand mimic helix. Structural comparisons of EFhd1, EFhd2, and AIF-1 revealed similarities in their overall structures. In the structure of the EFhd1 core domain, two Zn
ions were observed at the interface of the crystal contact, suggesting the possibility of Zn
-mediated multimerization. In addition, we found that EFhd1 has Ca
-independent β-actin-binding and Ca
-dependent β-actin-bundling activities. These findings suggest that EFhd1, an actin-binding and -bundling protein in the mitochondria, may contribute to the Ca
-dependent regulation of mitochondrial morphology and energy synthesis.
E2–25K/Hip2 is an unusual ubiquitin-conjugating enzyme that interacts with the frameshift mutant of ubiquitin B (UBB+1) and has been identified as a crucial factor regulating amyloid-β neurotoxicity. ...To study the structural basis of the neurotoxicity mediated by the E2–25K-UBB+1 interaction, we determined the three-dimensional structures of UBB+1, E2–25K and the E2–25K/ubiquitin, and E2–25K/UBB+1 complex. The structures revealed that ubiquitin or UBB+1 is bound to E2–25K via the enzyme MGF motif and residues in α9 of the enzyme. Polyubiquitylation assays together with analyses of various E2–25K mutants showed that disrupting UBB+1 binding markedly diminishes synthesis of neurotoxic UBB+1-anchored polyubiquitin. These results suggest that the interaction between E2–25K and UBB+1 is critical for the synthesis and accumulation of UBB+1-anchored polyubiquitin, which results in proteasomal inhibition and neuronal cell death.
HslVU is an ATP-dependent protease in bacteria consisting of HslV dodecamer and HslU hexamer. Upon ATP binding, HslU ATPase allosterically activates the catalytic function of HslV protease by 1–2 ...orders of magnitude. However, relatively little is known about the role of HslV in the control of HslU function. Here we describe the involvement of the N-terminal Thr active sites (Thr-1) of HslV in the communication between HslV and HslU. Binding of proteasome inhibitors to Thr-1 led to a dramatic increase in the interaction between HslV and HslU with a marked increase in ATP hydrolysis by HslU. Moreover, carbobenzoxy-leucyl-leucyl-leucinal (MG132) could bind to Thr-1 of free HslV, and this binding induced a tight interaction between HslV and HslU with the activation of HslU ATPase, suggesting that substrate-bound HslV can allosterically regulate HslU function. Unexpectedly, the deletion of Thr-1 also caused a dramatic increase in the affinity between HslV and HslU even in the absence of ATP. Furthermore, the increase in the number of the Thr-1 deletion mutant subunit in place of HslV subunit in a dodecamer led to a proportional increase in the affinity between HslV and HslU with gradual activation of HslU ATPase. Although the molecular mechanism elucidating how the Thr-1 deletion influences the interaction between HslV and HslU remains unknown, these results suggest an additional allosteric mechanism for the control of HslU function by HslV. Taken together, our findings indicate a critical involvement of Thr-1 of HslV in the reciprocal control of HslU function and, thus, for their communication.
Accumulation of β-catenin and subsequent stimulation of β-catenin-T cell-factor (Tcf)/lymphoid-enhancerfactor (Lef) transcriptional activity causes dedifferentiation of articular chondrocytes, which ...is characterized by decreased type II collagen expression and initiation of type I collagen expression. This study examined the mechanisms of α-catenin degradation, the role of α-catenin in β-catenin signaling, and the physiological significance of α-catenin regulation of β-catenin signaling in articular chondrocytes. We found that both α- and β-catenin accumulated during dedifferentiation of chondrocytes by escaping from proteasomal degradation. β-Catenin degradation was ubiquitination-dependent, whereas α-catenin was proteasomally degraded in a ubiquitination-independent fashion. The accumulated α- and β-catenin existed as complexes in the cytosol and nucleus. The complex formation between α- and β-catenin blocked proteasomal degradation of α-catenin and also inhibited β-catenin-Tcf/Lef transcriptional activity and the suppression of type II collagen expression associated with ectopic expression of β-catenin, the inhibition of proteasome, or Wnt signaling. Collectively, our results indicate that ubiquitin-independent degradation of α-catenin regulates β-catenin signaling and maintenance of the differentiated phenotype of articular chondrocytes.
NAmPRTase (PBEF/Visfatin) plays a pivotal role in the salvage pathway of NAD
+ biosynthesis. NAmPRTase has been an attractive target for anti-cancer agents that induce apoptosis of tumor cells via a ...declining plasma NAD
+ level. In this report, a series of structural analogs of FK866 (
1), a known NAmPRTase inhibitor, was synthesized and tested for inhibitory activities against the proliferation of cancer cells and human NAmPRTase. Among them, compound
7 showed similar anti-cancer and enzyme inhibitory activities to compound
1. Further investigation of compound
7 with X-ray analysis revealed a co-crystal structure in complex with human NAmPRTase, suggesting that Asp219 in the active site of the enzyme could contribute to an additional interaction with the pyrrole nitrogen of compound
7.
A NAmPRTase inhibitor, compound 7 showed anti-proliferative activity and the analysis of X-ray co-crystal structure suggested that Asp219 could contribute to an additional interaction with the pyrrole nitrogen of
7.
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► We designed and synthesized new FK866 analogs as NAmPRTase inhibitors. ► The new compounds were evaluated for the anti-cancer and enzyme inhibitory activities. ► X-ray co-crystal structure with the most potent compound, 7 was analyzed. ► Asp219 could contribute to an additional ionic interaction with the pyrrole nitrogen of compound
7.
Area-selective atomic layer deposition (AS-ALD) is a bottom-up fabrication technique that may revolutionize the semiconductor manufacturing process. Because the efficiency and applicability of AS-ALD ...strongly depend on the properties of the molecular precursors for deposition, the structural design and optimization of the precursors are strongly needed. With the aid of various modern computational chemistry tools, tailor-made molecular design of the ALD precursors for high deposition selectivity may become possible. In this Perspective, the requirements and challenges for the molecular properties of the AS-ALD precursors, as well as the theoretical design strategies for them, are discussed. Current approaches for the theoretical analysis and design of the AS-ALD processes and materials are reviewed. A possible simulation strategy for the various aspects of ALD and AS-ALD precursors is suggested.
One of the most important issues in the research related to Zn–air batteries is the hydrolysis of the aqueous solution. We have investigated the effectiveness of Zn ions and the anions of various ...acids as gas suppressants in the battery. Zn ions can function as a gas suppressant on a Pt surface, but they can stimulate additional gas production when they are deposited as Zn metal. On the other hand, the counter anions of weak acids behave as adsorbates to cover Zn metal effectively.
As previously reported, the activity of the large-conductance calcium (Ca(2+))-activated potassium (K(+)) (BK(Ca)) channel is strongly potentiated from the extracellular side of the cell membrane by ...certain benzofuroindole derivatives. Here, the mechanism of action of one of the most potent activators, 4-chloro-7-(trifluoromethyl)-10H-benzofuro3,2-bindole-1-carboxylic acid (CTBIC), is characterized. This compound, Compound 22 in the previous report (Chembiochem 6:1745-1748, 2005), potentiated the activity of the channel by shifting its conductance-voltage relationship toward the more negative direction. Cotreatment with CTBIC reduced the affinity of charybdotoxin, a peptide pore-blocker, whereas that of tetraethylammonium, a small pore-blocking quaternary ammonium, was not significantly altered. Guided by these results, scanning mutagenesis of the outer vestibule of the BK(Ca) channel was launched to uncover the molecular determinants that affect CTBIC binding. Alanine substitution of several amino acid residues in the turret region and the S6 helix of the channel decreased potentiation by CTBIC. Homology modeling and molecular dynamics simulation showed that some of these residues formed a CTBIC binding pocket between two adjacent α-subunits in the outer vestibule of the channel. Thus, it can be envisioned that benzofuroindole derivatives stabilize the open conformation of the channel by binding to the residues clustered across the extracellular part of the subunit interface. The present results indicate that the interface between different α-subunits of the BK(Ca) channel may play a critical role in the modulation of channel activity. Therefore, this interface represents a potential therapeutic target site for the regulation of K(+) channels.
Quinolinate phosphoribosyltransferase (QPRT) catalyses the production of nicotinic acid mononucleotide, a precursor of de novo biosynthesis of the ubiquitous coenzyme nicotinamide adenine ...dinucleotide. QPRT is also essential for maintaining the homeostasis of quinolinic acid in the brain, a possible neurotoxin causing various neurodegenerative diseases. Although QPRT has been extensively analysed, the molecular basis of the reaction catalysed by human QPRT remains unclear. Here, we present the crystal structures of hexameric human QPRT in the apo form and its complexes with reactant or product. We found that the interaction between dimeric subunits was dramatically altered during the reaction process by conformational changes of two flexible loops in the active site at the dimer-dimer interface. In addition, the N-terminal short helix α1 was identified as a critical hexamer stabilizer. The structural features, size distribution, heat aggregation and ITC studies of the full-length enzyme and the enzyme lacking helix α1 strongly suggest that human QPRT acts as a hexamer for cooperative reactant binding via three dimeric subunits and maintaining stability. Based on our comparison of human QPRT structures in the apo and complex forms, we propose a drug design strategy targeting malignant glioma.
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