Membrane orientation and oligomerization of the melanocortin receptor accessory protein 2 [Metabolism]
In this study, we demonstrate that the conserved polybasic motif that dictates the membrane topology and dimerization of MRAP1 does not control the membrane orientation and dimerization of MRAP2. We also show that MRAP2 dimerizes through its transmembrane domain and can form higher-order oligomers that arrange MRAP2 monomers in a parallel orientation. Investigating the molecular details of MRAP2 structure is essential for understanding the mechanism by which it regulates G protein–coupled receptors and will aid in elucidating the pathways involved in metabolic dysfunction. (Source: Journal of Biological Chemistry)
Source: Journal of Biological Chemistry - November 27, 2020 Category: Chemistry Authors: Valerie Chen, Antonio E. Bruno, Laura L. Britt, Ciria C. Hernandez, Luis E. Gimenez, Alys Peisley, Roger D. Cone, Glenn L. Millhauser Tags: Metabolism Source Type: research
Low-dose naltrexone rescues inflammation and insulin resistance associated with hyperinsulinemia [Signal Transduction]
The incidence of diabetes, obesity, and metabolic diseases has reached an epidemic status worldwide. Insulin resistance is a common link in the development of these conditions, and hyperinsulinemia is a central hallmark of peripheral insulin resistance. However, how hyperinsulinemia leads to systemic insulin resistance is less clear. We now provide evidence that hyperinsulinemia promotes the release of soluble pro-inflammatory mediators from macrophages that lead to systemic insulin resistance. Our observations suggest that hyperinsulinemia induces sirtuin1 (SIRT1) repression and stimulates NF-κB p65 nuclear translocation...
Source: Journal of Biological Chemistry - November 27, 2020 Category: Chemistry Authors: Abhinav Choubey, Khyati Girdhar, Aditya K. Kar, Shaivya Kushwaha, Manoj Kumar Yadav, Debabrata Ghosh, Prosenjit Mondal Tags: Metabolism Source Type: research
The solution structure of the complement deregulator FHR5 reveals a compact dimer and provides new insights into CFHR5 nephropathy [Protein Structure and Folding]
The human complement Factor H–related 5 protein (FHR5) antagonizes the main circulating complement regulator Factor H, resulting in the deregulation of complement activation. FHR5 normally contains nine short complement regulator (SCR) domains, but a FHR5 mutant has been identified with a duplicated N-terminal SCR-1/2 domain pair that causes CFHR5 nephropathy. To understand how this duplication causes disease, we characterized the solution structure of native FHR5 by analytical ultracentrifugation and small-angle X-ray scattering. Sedimentation velocity and X-ray scattering indicated that FHR5 was dimeric, with a radius ...
Source: Journal of Biological Chemistry - November 27, 2020 Category: Chemistry Authors: Nilufar Kadkhodayi-Kholghi, Jayesh S. Bhatt, Jayesh Gor, Lindsay C. McDermott, Daniel P. Gale, Stephen J. Perkins Tags: Immunology Source Type: research
SOX9 promotes stress-responsive transcription of VGF nerve growth factor inducible gene in renal tubular epithelial cells [Gene Regulation]
Acute kidney injury (AKI) is a common clinical condition associated with diverse etiologies and abrupt loss of renal function. In patients with sepsis, rhabdomyolysis, cancer, and cardiovascular disorders, the underlying disease or associated therapeutic interventions can cause hypoxia, cytotoxicity, and inflammatory insults to renal tubular epithelial cells (RTECs), resulting in the onset of AKI. To uncover stress-responsive disease-modifying genes, here we have carried out renal transcriptome profiling in three distinct murine models of AKI. We find that Vgf nerve growth factor inducible gene up-regulation is a common tr...
Source: Journal of Biological Chemistry - November 27, 2020 Category: Chemistry Authors: Ji Young Kim, Yuntao Bai, Laura A. Jayne, Ferdos Abdulkader, Megha Gandhi, Tayla Perreau, Samir V. Parikh, David S. Gardner, Alan J. Davidson, Veronika Sander, Min-Ae Song, Amandeep Bajwa, Navjot Singh Pabla Tags: Molecular Bases of Disease Source Type: research
TL1A inhibits atherosclerosis in apoE-deficient mice by regulating the phenotype of vascular smooth muscle cells [Lipids]
In this study, we determined the precise effects of TL1A on the development of atherosclerosis and the underlying mechanisms in apoE-deficient mice. After 12 weeks of pro-atherogenic high-fat diet feeding and TL1A treatment, mouse aorta, serum, and liver samples were collected and used to assess atherosclerotic lesions, fatty liver, and expression of related molecules. We found that TL1A treatment significantly reduced lesions and enhanced plaque stability. Mechanistically, TL1A inhibited formation of foam cells derived from vascular smooth muscle cells (VSMCs) but not macrophages by activating expression of ABC transporte...
Source: Journal of Biological Chemistry - November 27, 2020 Category: Chemistry Authors: Dan Zhao, Jiaqi Li, Chao Xue, Ke Feng, Lipei Liu, Peng Zeng, Xiaolin Wang, Yuanli Chen, Luyuan Li, Zhisong Zhang, Yajun Duan, Jihong Han, Xiaoxiao Yang Tags: Molecular Bases of Disease Source Type: research
TET is targeted for proteasomal degradation by the PHD-pVHL pathway to reduce DNA hydroxymethylation [Signal Transduction]
Hypoxia-inducible factors are heterodimeric transcription factors that play a crucial role in a cell's ability to adapt to low oxygen. The von Hippel-Lindau tumor suppressor (pVHL) acts as a master regulator of HIF activity, and its targeting of prolyl hydroxylated HIF-α for proteasomal degradation under normoxia is thought to be a major mechanism for pVHL tumor suppression and cellular response to oxygen. Whether pVHL regulates other targets through a similar mechanism is largely unknown. Here, we identify TET2/3 as novel targets of pVHL. pVHL induces proteasomal degradation of TET2/3, resulting in reduced global 5-hydro...
Source: Journal of Biological Chemistry - November 27, 2020 Category: Chemistry Authors: Sijia Fan, Jing Wang, Guangqing Yu, Fangjing Rong, Dawei Zhang, Chenxi Xu, Juan Du, Zhi Li, Gang Ouyang, Wuhan Xiao Tags: Gene Regulation Source Type: research
Pex3 confines pexophagy receptor activity of Atg36 to peroxisomes by regulating Hrr25-mediated phosphorylation and proteasomal degradation [Cell Biology]
In macroautophagy (hereafter autophagy), cytoplasmic molecules and organelles are randomly or selectively sequestered within double-membrane vesicles called autophagosomes and delivered to lysosomes or vacuoles for degradation. In selective autophagy, the specificity of degradation targets is determined by autophagy receptors. In the budding yeast Saccharomyces cerevisiae, autophagy receptors interact with specific targets and Atg11, resulting in the recruitment of a protein complex that initiates autophagosome formation. Previous studies have revealed that autophagy receptors are regulated by posttranslational modificatio...
Source: Journal of Biological Chemistry - November 27, 2020 Category: Chemistry Authors: Sota Meguro, Xizhen Zhuang, Hiromi Kirisako, Hitoshi Nakatogawa Tags: Cell Biology Source Type: research
The extent of cyclin C promoter occupancy directs changes in stress-dependent transcription [Molecular Bases of Disease]
In conclusion, this study revealed that different stress stimuli elicit specific changes in CKM promoter occupancy correlating to altered transcriptional outputs. Finally, although CKM components were recruited or expelled from promoters as a unit, heterogeneity was observed at individual promoters, suggesting a mechanism to generate gene- and stress-specific responses. (Source: Journal of Biological Chemistry)
Source: Journal of Biological Chemistry - November 27, 2020 Category: Chemistry Authors: David C. Stieg, Katrina F. Cooper, Randy Strich Tags: Gene Regulation Source Type: research
The Ig-like domain of Punctin/MADD-4 is the primary determinant for interaction with the ectodomain of neuroligin NLG-1 [Molecular Biophysics]
Punctin/MADD-4, a member of the ADAMTSL extracellular matrix protein family, was identified as an anterograde synaptic organizer in the nematode Caenorhabditis elegans. At GABAergic neuromuscular junctions, the short isoform MADD-4B binds the ectodomain of neuroligin NLG-1, itself a postsynaptic organizer of inhibitory synapses. To identify the molecular bases of their partnership, we generated recombinant forms of the two proteins and carried out a comprehensive biochemical and biophysical study of their interaction, complemented by an in vivo localization study. We show that spontaneous proteolysis of MADD-4B first gener...
Source: Journal of Biological Chemistry - November 27, 2020 Category: Chemistry Authors: Semeli Platsaki, Xin Zhou, Berangere Pinan–Lucarre, Vincent Delauzun, Haiȷun Tu, Pascal Mansuelle, Patrick Fourquet, Yves Bourne, Jean–Louis Bessereau, Pascale Marchot Tags: Neurobiology Source Type: research
Gallic acid is a dual {alpha}/{beta}-secretase modulator that reverses cognitive impairment and remediates pathology in Alzheimer mice [Neurobiology]
Several plant-derived compounds have demonstrated efficacy in pre-clinical Alzheimer's disease (AD) rodent models. Each of these compounds share a gallic acid (GA) moiety, and initial assays on this isolated molecule indicated that it might be responsible for the therapeutic benefits observed. To test this hypothesis in a more physiologically relevant setting, we investigated the effect of GA in the mutant human amyloid β-protein precursor/presenilin 1 (APP/PS1) transgenic AD mouse model. Beginning at 12 months, we orally administered GA (20 mg/kg) or vehicle once daily for 6 months to APP/PS1 mice that have accelerated A...
Source: Journal of Biological Chemistry - November 27, 2020 Category: Chemistry Authors: Takashi Mori, Naoki Koyama, Tomotaka Yokoo, Tatsuya Segawa, Masahiro Maeda, Darrell Sawmiller, Jun Tan, Terrence Town Tags: Molecular Bases of Disease Source Type: research
CaMKK2 is inactivated by cAMP-PKA signaling and 14-3-3 adaptor proteins [Enzymology]
The calcium-calmodulin–dependent protein kinase kinase-2 (CaMKK2) is a key regulator of cellular and whole-body energy metabolism. It is known to be activated by increases in intracellular Ca2+, but the mechanisms by which it is inactivated are less clear. CaMKK2 inhibition protects against prostate cancer, hepatocellular carcinoma, and metabolic derangements induced by a high-fat diet; therefore, elucidating the intracellular mechanisms that inactivate CaMKK2 has important therapeutic implications. Here we show that stimulation of cAMP-dependent protein kinase A (PKA) signaling in cells inactivates CaMKK2 by phosphoryla...
Source: Journal of Biological Chemistry - November 27, 2020 Category: Chemistry Authors: Christopher G. Langendorf, Matthew T. O'Brien, Kevin R. W. Ngoei, Luke M. McAloon, Urmi Dhagat, Ashfaqul Hoque, Naomi X. Y. Ling, Toby A. Dite, Sandra Galic, Kim Loh, Michael W. Parker, Jonathan S. Oakhill, Bruce E. Kemp, John W. Scott Tags: Signal Transduction Source Type: research
Mutant thermal proteome profiling for characterization of missense protein variants and their associated phenotypes within the proteome [Protein Structure and Folding]
This study characterized global impacts of temperature sensitivity–inducing missense mutations in two different subunits of the 26S proteasome. The majority of alterations identified by RNA-Seq and global proteomics were similar between the mutants, which could suggest that a similar functional disruption is occurring in both missense variants. Results from mTPP, however, provide unique insights into the mechanisms that contribute to the TS phenotype in each mutant, revealing distinct changes that were not obtained using only steady-state transcriptome and proteome analyses. Computationally, multisite λ-dynamics simulat...
Source: Journal of Biological Chemistry - November 27, 2020 Category: Chemistry Authors: Sarah A. Peck Justice, Monica P. Barron, Guihong D. Qi, H. R. Sagara Wiȷeratne, Jose F. Victorino, Ed R. Simpson, Jonah Z. Vilseck, Aruna B. Wiȷeratne, Amber L. Mosley Tags: Genomics and Proteomics Source Type: research
The energetic cost of NNT-dependent ROS removal [Metabolism]
Under conditions of high nutrient availability and low ATP synthesis, mitochondria generate reactive oxygen species (ROS) that must be removed to avoid cell injury. Among the enzymes involved in this scavenging process, peroxidases play a crucial role, using NADPH provided mostly by nicotinamide nucleotide transhydrogenase (NNT). However, scarce information is available on how and to what extent ROS formation is linked to mitochondrial oxygen consumption. A new study by Smith et al. shows that NNT activity maintains low ROS levels by means of a fine modulation of mitochondrial oxygen utilization. (Source: Journal of Biological Chemistry)
Source: Journal of Biological Chemistry - November 27, 2020 Category: Chemistry Authors: Nina Kaludercic, Fabio Di Lisa Tags: Editors ' Picks Highlights Source Type: research
Flux through mitochondrial redox circuits linked to nicotinamide nucleotide transhydrogenase generates counterbalance changes in energy expenditure [Metabolism]
Compensatory changes in energy expenditure occur in response to positive and negative energy balance, but the underlying mechanism remains unclear. Under low energy demand, the mitochondrial electron transport system is particularly sensitive to added energy supply (i.e. reductive stress), which exponentially increases the rate of H2O2 (JH2O2) production. H2O2 is reduced to H2O by electrons supplied by NADPH. NADP+ is reduced back to NADPH by activation of mitochondrial membrane potential–dependent nicotinamide nucleotide transhydrogenase (NNT). The coupling of reductive stress-induced JH2O2 production to NNT-linked redo...
Source: Journal of Biological Chemistry - November 27, 2020 Category: Chemistry Authors: Cody D. Smith, Cameron A. Schmidt, Chien-Te Lin, Kelsey H. Fisher-Wellman, P. Darrell Neufer Tags: Editors ' Picks Source Type: research
A heterologous in-cell assay for investigating intermicrovillar adhesion complex interactions reveals a novel protrusion length-matching mechanism [Developmental Biology]
Solute transporting epithelial cells build arrays of microvilli on their apical surface to increase membrane scaffolding capacity and enhance function potential. In epithelial tissues such as the kidney and gut, microvilli are length-matched and assembled into tightly packed “brush borders,” which are organized by ∼50-nm thread-like links that form between the distal tips of adjacent protrusions. Composed of protocadherins CDHR2 and CDHR5, adhesion links are stabilized at the tips by a cytoplasmic tripartite module containing the scaffolds USH1C and ANKS4B and the actin-based motor MYO7B. Because several questions ab...
Source: Journal of Biological Chemistry - November 27, 2020 Category: Chemistry Authors: Meredith L. Weck, Scott W. Crawley, Matthew J. Tyska Tags: Editors ' Picks Source Type: research
