Read by QxMD icon Read


Alejandro Parrales, Atul Ranjan, Swathi V Iyer, Subhash Padhye, Scott J Weir, Anuradha Roy, Tomoo Iwakuma
Stabilization of mutant p53 (mutp53) in tumours greatly contributes to malignant progression. However, little is known about the underlying mechanisms and therapeutic approaches to destabilize mutp53. Here, through high-throughput screening we identify statins, cholesterol-lowering drugs, as degradation inducers for conformational or misfolded p53 mutants with minimal effects on wild-type p53 (wtp53) and DNA contact mutants. Statins preferentially suppress mutp53-expressing cancer cell growth. Specific reduction of mevalonate-5-phosphate by statins or mevalonate kinase knockdown induces CHIP ubiquitin ligase-mediated nuclear export, ubiquitylation, and degradation of mutp53 by impairing interaction of mutp53 with DNAJA1, a Hsp40 family member...
October 24, 2016: Nature Cell Biology
Fabrizio Bernini, Daniele Malferrari, Marcello Pignataro, Carlo Augusto Bortolotti, Giulia Di Rocco, Lidia Lancellotti, Maria Franca Brigatti, Rakez Kayed, Marco Borsari, Federica Del Monte, Elena Castellini
The pathological hallmark of misfolded protein diseases and aging is the accumulation of proteotoxic aggregates. However, the mechanisms of proteotoxicity and the dynamic changes in fiber formation and dissemination remain unclear, preventing a cure. Here we adopted a reductionist approach and used atomic force microscopy to define the temporal and spatial changes of amyloid aggregates, their modes of dissemination and the biochemical changes that may influence their growth. We show that pre-amyloid oligomers (PAO) mature to form linear and circular protofibrils, and amyloid fibers, and those can break reforming PAO that can migrate invading neighbor structures...
October 24, 2016: Scientific Reports
Seila Omer, Timothy J Harlow, Johann Peter Gogarten
Finding a signature of purifying selection in a gene is usually interpreted as evidence for the gene providing a function that is targeted by natural selection. This opinion offers a very different hypothesis: purifying selection may be due to removing harmful mutations from the population, that is, the gene and its encoded protein become harmful after a mutation occurred, possibly because the mutated protein interferes with the translation machinery, or because of toxicity of the misfolded protein. Finding a signature of purifying selection should not automatically be considered proof of the gene's selectable function...
October 20, 2016: Trends in Microbiology
Dennis W Piehl, Luis M Blancas-Mejía, Marina Ramirez-Alvarado, Chad M Rienstra
Light chain (AL) amyloidosis is a systemic disease characterized by the formation of immunoglobulin light-chain fibrils in critical organs of the body. The light-chain protein AL-09 presents one severe case of cardiac AL amyloidosis, which contains seven mutations in the variable domain (VL) relative to its germline counterpart, κI O18/O8 VL. Three of these mutations are non-conservative-Y87H, N34I, and K42Q-and previous work has shown that they are responsible for significantly reducing the protein's thermodynamic stability, allowing fibril formation to occur with fast kinetics and across a wide-range of pH conditions...
October 22, 2016: Biomolecular NMR Assignments
Shobini Jayaraman, Jose Luis Sánchez-Quesada, Olga Gursky
Lipids in the body are transported via lipoproteins that are nanoparticles comprised of lipids and amphipathic proteins termed apolipoproteins. This family of lipid surface-binding proteins is over-represented in human amyloid diseases. In particular, all major proteins of high-density lipoproteins (HDL), including apoA-I, apoA-II and serum amyloid A, can cause systemic amyloidoses in humans upon protein mutations, post-translational modifications or overproduction. Here, we begin to explore how the HDL lipid composition influences amyloid deposition by apoA-I and related proteins...
October 18, 2016: Biochimica et Biophysica Acta
Jennifer L Smith, Corey L Anderson, Don E Burgess, Claude S Elayi, Craig T January, Brian P Delisle
The molecular mechanisms underlying congenital long QT syndrome (LQTS) are now beginning to be understood. New insights into the etiology and therapeutic strategies are emerging from heterologous expression studies of LQTS-linked mutant proteins, as well as inducible pluripotent stem cell derived cardiomyocytes (iPSC-CMs) from LQTS patients. This review focuses on the major molecular mechanism that underlies LQTS type 2 (LQT2). LQT2 is caused by loss of function (LOF) mutations in KCNH2 (also known as the human Ether-à-go-go-Related Gene or hERG)...
October 2016: Journal of Arrhythmia
Tara M Weitz, Terrence Town
In a recent issue of Nature, Sevigny et al. (2016) report findings from a phase 1b clinical trial of aducanumab (a monoclonal antibody targeting misfolded amyloid-β peptides), revitalizing the "amyloid cascade hypothesis" and bringing mononuclear phagocytes center stage in the treatment of Alzheimer's disease.
October 18, 2016: Immunity
Xiaoyu Zhuang, Bing Zhao, Shu Liu, Fengrui Song, Fengchao Cui, Zhiqiang Liu, Yunqi Li
Misfolding and aggregation of Cu, Zn superoxide dismutase (SOD1) is implicated in the etiology amyotrophic lateral sclerosis (ALS). The use of small molecules may stabilize the spatial structure of SOD1 dimer, thus preventing its dissociation and aggregation. In this study, "native" mass spectrometry (MS) was used to study the non-covalent interactions between SOD1 and flavonoid compounds. MS experiments were performed on a quadruple time-of-flight (Q-ToF) mass spectrometer with an electrospray ionization (ESI) source and T-wave ion mobility...
October 19, 2016: Analytical Chemistry
Ying Wei, Jun Lu, Tong Lu, Feihong Meng, Jia Xu, Li Wang, Yang Li, Liping Wang, Fei Li
Prefibrillar amyloid aggregates of proteins are known as cytotoxic species and a common pathogenic factor for many degenerative diseases. The mechanism underlying the formation and cytotoxicity of prefibrillar aggregates is believed to be independent of the actual nature of the amyloid protein. In this study, we monitored the formation of the peptide oligomers and examined the disruptive effects of the oligomers on liposomes using the human islet amyloid polypeptide fragment hIAPP18-27 as a model peptide. We observed various morphologies of oligomers formed at different aggregation stages that precede the formation of mature amyloid fibrils...
October 19, 2016: Physical Chemistry Chemical Physics: PCCP
Vibhuti Joshi, Ayeman Amanullah, Arun Upadhyay, Ribhav Mishra, Amit Kumar, Amit Mishra
Cells regularly synthesize new proteins to replace old and abnormal proteins for normal cellular functions. Two significant protein quality control pathways inside the cellular milieu are ubiquitin proteasome system (UPS) and autophagy. Autophagy is known for bulk clearance of cytoplasmic aggregated proteins, whereas the specificity of protein degradation by UPS comes from E3 ubiquitin ligases. Few E3 ubiquitin ligases, like C-terminus of Hsc70-interacting protein (CHIP) not only take part in protein quality control pathways, but also plays a key regulatory role in other cellular processes like signaling, development, DNA damage repair, immunity and aging...
2016: Frontiers in Molecular Neuroscience
Kamalakshi Deka, Archana Singh, Surajit Chakraborty, Rupak Mukhopadhyay, Sougata Saha
ATE1-mediated post-translational addition of arginine to a protein has been shown to regulate activity, interaction, and stability of the protein substrates. Arginylation has been linked to many different stress conditions, namely ER stress, cytosolic misfolded protein stress, and nitrosative stress. However, clear understanding about the effect of arginylation in cellular stress responses is yet to emerge. In this study, we investigated the role of arginylation in heat-stress response. Our findings suggest that Ate1 knock out (KO) cells are more susceptible to heat stress compared with its wild-type counterparts due to the induction of apoptosis in KO cells...
2016: Cell Death Discovery
Mansi R Khanna, Jane Kovalevich, Virginia M-Y Lee, John Q Trojanowski, Kurt R Brunden
A group of neurodegenerative diseases referred to as tauopathies are characterized by the presence of brain cells harboring inclusions of pathological species of the tau protein. These disorders include Alzheimer's disease and frontotemporal lobar degeneration due to tau pathology, including progressive supranuclear palsy, corticobasal degeneration, and Pick's disease. Tau is normally a microtubule (MT)-associated protein that appears to play an important role in ensuring proper axonal transport, but in tauopathies tau becomes hyperphosphorylated and disengages from MTs, with consequent misfolding and deposition into inclusions that mainly affect neurons but also glia...
October 2016: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
Fiorenza Fumagalli, Julia Noack, Timothy J Bergmann, Eduardo Cebollero Presmanes, Giorgia Brambilla Pisoni, Elisa Fasana, Ilaria Fregno, Carmela Galli, Marisa Loi, Tatiana Soldà, Rocco D'Antuono, Andrea Raimondi, Martin Jung, Armin Melnyk, Stefan Schorr, Anne Schreiber, Luca Simonelli, Luca Varani, Caroline Wilson-Zbinden, Oliver Zerbe, Kay Hofmann, Matthias Peter, Manfredo Quadroni, Richard Zimmermann, Maurizio Molinari
The endoplasmic reticulum (ER) is a site of protein biogenesis in eukaryotic cells. Perturbing ER homeostasis activates stress programs collectively called the unfolded protein response (UPR). The UPR enhances production of ER-resident chaperones and enzymes to reduce the burden of misfolded proteins. On resolution of ER stress, ill-defined, selective autophagic programs remove excess ER components. Here we identify Sec62, a constituent of the translocon complex regulating protein import in the mammalian ER, as an ER-resident autophagy receptor...
October 17, 2016: Nature Cell Biology
Rosemary J Jackson, Nikita Rudinskiy, Abigail G Herrmann, Shaun Croft, JeeSoo Monica Kim, Veselina Petrova, Juan Jose Ramos-Rodriguez, Rose Pitstick, Susanne Wegmann, Monica Garcia-Alloza, George A Carlson, Bradley T Hyman, Tara L Spires-Jones
Alzheimer's disease is characterized by the presence of aggregates of amyloid beta (Aβ) in senile plaques and tau in neurofibrillary tangles, as well as marked neuron and synapse loss. Of these pathological changes, synapse loss correlates most strongly with cognitive decline. Synapse loss occurs prominently around plaques due to accumulations of oligomeric Aβ. Recent evidence suggests that tau may also play a role in synapse loss but the interactions of Aβ and tau in synapse loss remain to be determined...
October 17, 2016: European Journal of Neuroscience
Romana Parveen, Tooba Naz Shamsi, Sadaf Fatima
This review helps to understand protein misfolding events, which results in protein aggregation, and hence to related neurodegenerative diseases. Many chaperones and folding factors are found inside the cell system for the proper folding of protein. If protein gets misfolded, it may accumulate in cells and can lead to several fatal diseases. In some cases, misfolded proteins aggregated in form of loop-sheet polymer and amyloid fibril when they escape the degradation process and leads to neurodegenerative disorders...
October 13, 2016: International Journal of Biological Macromolecules
Cody S Shirriff, John J Heikkila
Endoplasmic reticulum (ER) stress can result in the accumulation of unfolded/misfolded protein in the ER lumen, which can trigger the unfolded protein response (UPR) resulting in the activation of various genes including immunoglobulin-binding protein (BiP; also known as glucose-regulated protein 78 or HSPA5). BiP, an ER heat shock protein 70 (HSP70) family member, binds to unfolded protein, inhibits their aggregation and re-folds them in an ATP-dependent manner. While cadmium, an environmental contaminant, was shown to induce the accumulation of HSP70 in vertebrate cells, less information is available regarding the effect of this metal on BiP accumulation or function...
October 13, 2016: Comparative Biochemistry and Physiology. Toxicology & Pharmacology: CBP
Ranjeet Kumar, Candan Ariöz, Yaozong Li, Niklas Bosaeus, Sandra Rocha, Pernilla Wittung-Stafshede
After cellular uptake, Copper (Cu) ions are transferred from the chaperone Atox1 to the Wilson disease protein (ATP7B) for incorporation into Cu-dependent enzymes in the secretory pathway. Human ATP7B is a large multi-domain membrane-spanning protein which, in contrast to homologues in other organisms, has six similar cytoplasmic metal-binding domains (MBDs). The reason for multiple MBDs is proposed to be indirect modulation of enzymatic activity and it is thus intriguing that point mutations in MBDs can promote Wilson disease...
October 15, 2016: Biometals: An International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine
Yael Bar-Lavan, Netta Shemesh, Anat Ben-Zvi
Quality control is an essential aspect of cellular function, with protein folding quality control being carried out by molecular chaperones, a diverse group of highly conserved proteins that specifically identify misfolded conformations. Molecular chaperones are thus required to support proteins affected by expressed polymorphisms, mutations, intrinsic errors in gene expression, chronic insult or the acute effects of the environment, all of which contribute to a flux of metastable proteins. In this article, we review the four main chaperone families in metazoans, namely Hsp60 (where Hsp is heat-shock protein), Hsp70, Hsp90 and sHsps (small heat-shock proteins), as well as their co-chaperones...
October 15, 2016: Essays in Biochemistry
Kathleen McCaffrey, Ineke Braakman
The ER (endoplasmic reticulum) is the protein folding 'factory' of the secretory pathway. Virtually all proteins destined for the plasma membrane, the extracellular space or other secretory compartments undergo folding and maturation within the ER. The ER hosts a unique PQC (protein quality control) system that allows specialized modifications such as glycosylation and disulfide bond formation essential for the correct folding and function of many secretory proteins. It is also the major checkpoint for misfolded or aggregation-prone proteins that may be toxic to the cell or extracellular environment...
October 15, 2016: Essays in Biochemistry
Wolfgang Voos, Witold Jaworek, Anne Wilkening, Michael Bruderek
Mitochondria are essential constituents of a eukaryotic cell by supplying ATP and contributing to many mayor metabolic processes. As endosymbiotic organelles, they represent a cellular subcompartment exhibiting many autonomous functions, most importantly containing a complete endogenous machinery responsible for protein expression, folding and degradation. This article summarizes the biochemical processes and the enzymatic components that are responsible for maintaining mitochondrial protein homoeostasis. As mitochondria lack a large part of the required genetic information, most proteins are synthesized in the cytosol and imported into the organelle...
October 15, 2016: Essays in Biochemistry
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"