Showing papers by "David Eisenberg published in 2019"
23 Sep 2019
TL;DR: Evidence is presented for the ability of a single amino acid to self-assemble into a potent and stable catalytic structural entity showing catalytic properties similar to those of the natural enzyme carbonic anhydrase.
Abstract: Enzymatic activity is crucial for various technological applications, yet the complex structures and limited stability of enzymes often hinder their use. Hence, de novo design of robust biocatalysts that are much simpler than their natural counterparts and possess enhanced catalytic activity has long been a goal in biotechnology. Here, we present evidence for the ability of a single amino acid to self-assemble into a potent and stable catalytic structural entity. Spontaneously, phenylalanine (F) molecules coordinate with zinc ions to form a robust, layered, supramolecular amyloid-like ordered architecture (F-Zn(ii)) and exhibit remarkable carbonic anhydrase-like catalytic activity. Notably, amongst the reported artificial biomolecular hydrolases, F-Zn(ii) displays the lowest molecular mass and highest catalytic efficiency, in addition to reusability, thermal stability, substrate specificity, stereoselectivity and rapid catalytic CO2 hydration ability. Thus, this report provides a rational path towards future de novo design of minimalistic biocatalysts for biotechnological and industrial applications.
114 citations
TL;DR: Cryo-EM analyses of α-synuclein fibrils formed with hereditary Parkinson's disease mutant H50Q reveal features that help explain the mutant’s properties in vitro and in cells.
Abstract: Deposits of amyloid fibrils of α-synuclein are the histological hallmarks of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, with hereditary mutations in α-synuclein linked to the first two of these conditions. Seeing the changes to the structures of amyloid fibrils bearing these mutations may help to understand these diseases. To this end, we determined the cryo-EM structures of α-synuclein fibrils containing the H50Q hereditary mutation. We find that the H50Q mutation results in two previously unobserved polymorphs of α-synuclein: narrow and wide fibrils, formed from either one or two protofilaments, respectively. These structures recapitulate conserved features of the wild-type fold but reveal new structural elements, including a previously unobserved hydrogen-bond network and surprising new protofilament arrangements. The structures of the H50Q polymorphs help to rationalize the faster aggregation kinetics, higher seeding capacity in biosensor cells and greater cytotoxicity that we observe for H50Q compared to wild-type α-synuclein.
113 citations
TL;DR: The structures reveal the polymorphic nature of TDP-43 and suggest how the A315E mutation converts the R-shaped polymorph to an irreversible form that enhances pathology.
Abstract: The DNA and RNA processing protein TDP-43 undergoes both functional and pathogenic aggregation. Functional TDP-43 aggregates form reversible, transient species such as nuclear bodies, stress granules, and myo-granules. Pathogenic, irreversible TDP-43 aggregates form in amyotrophic lateral sclerosis and other neurodegenerative conditions. Here we find the features of TDP-43 fibrils that confer both reversibility and irreversibility by determining structures of two segments reported to be the pathogenic cores of human TDP-43 aggregation: SegA (residues 311-360), which forms three polymorphs, all with dagger-shaped folds; and SegB A315E (residues 286-331 containing the amyotrophic lateral sclerosis hereditary mutation A315E), which forms R-shaped folds. Energetic analysis suggests that the dagger-shaped polymorphs represent irreversible fibril structures, whereas the SegB polymorph may participate in both reversible and irreversible fibrils. Our structures reveal the polymorphic nature of TDP-43 and suggest how the A315E mutation converts the R-shaped polymorph to an irreversible form that enhances pathology.
104 citations
TL;DR: The ability of these inhibitors to interfere with both Aβ and tau seeds suggests these fibrils share a common epitope, and supports the hypothesis that cross-seeding is one mechanism by which amyloid is linked to tau aggregation and could promote cognitive decline.
Abstract: Alzheimer's disease (AD) pathology is characterized by plaques of amyloid beta (Aβ) and neurofibrillary tangles of tau. Aβ aggregation is thought to occur at early stages of the disease, and ultimately gives way to the formation of tau tangles which track with cognitive decline in humans. Here, we report the crystal structure of an Aβ core segment determined by MicroED and in it, note characteristics of both fibrillar and oligomeric structure. Using this structure, we designed peptide-based inhibitors that reduce Aβ aggregation and toxicity of already-aggregated species. Unexpectedly, we also found that these inhibitors reduce the efficiency of Aβ-mediated tau aggregation, and moreover reduce aggregation and self-seeding of tau fibrils. The ability of these inhibitors to interfere with both Aβ and tau seeds suggests these fibrils share a common epitope, and supports the hypothesis that cross-seeding is one mechanism by which amyloid is linked to tau aggregation and could promote cognitive decline.
80 citations
TL;DR: The structure of amyloid fibrils formed by two segments previously reported to be the pathogenic cores of TDP-43 aggregation are determined and suggest how the A315E mutation may convert this polymorph to the irreversible type and lead to mutation-enhanced pathology.
Abstract: Summary Paragraph TDP-43 is an essential DNA/RNA processing protein that undergoes both functional and pathogenic aggregation. Functional TDP-43 aggregates are reversible, forming transient species such as nuclear bodies, stress granules, and myo-granules1–3. In contrast pathogenic TDP-43 aggregates are irreversible, forming stable intracellular amyloid-like inclusions4,5. These inclusions are the primary pathology of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP)6. Disease-associated, hereditary mutations in TDP-43 are known to accelerate the deposition of irreversible aggregates in the cytoplasm7. Reversible TDP-43 aggregation has been shown to precede the formation of irreversible amyloid fibrils similar to the behavior of proteins hnRNPA1 and FUS8–10. Still unknown, however, are the structural features of TDP-43 fibrils that confer both reversibility and irreversibility and how hereditary mutations can impose irreversible aggregation. Here, we determined the structures of amyloid fibrils formed by two segments previously reported to be the pathogenic cores of TDP-43 aggregation7,11,12; these are termed SegA (residues 311-360) and SegB A315E (residues 286-331 containing the ALS hereditary mutation A315E). SegA forms three polymorphs, all with dagger-shaped folds. SegB forms R-shaped folds. All four polymorphs have folds confined to two dimensions, and are stabilized by hydrophobic cores and peripheral hydrogen bonds. Energetic analysis suggests that the dagger-shaped polymorphs are examples of the irreversible fibril structures of TDP-43, whereas the SegB polymorph may participate in both reversible and irreversible fibril structure. Our structure suggests how the A315E mutation may convert this polymorph to the irreversible type and lead to mutation-enhanced pathology.
61 citations
TL;DR: The study of the structure of a variant α-synuclein inherited in families afflicted with a clinical picture of parkinsonism and Lewy Body Dementia supplements recent structures of the wild type structure, and shows how a single residue change can result in a greatly changed structure that may underlie the inherited form of the disease.
Abstract: Aggregation of α-synuclein is a defining molecular feature of Parkinson9s disease, Lewy Body Dementia, and Multiple Systems Atrophy. Hereditary mutations in α-synuclein are linked to both Parkinson9s disease and Lewy Body Dementia; in particular, patients bearing the E46K disease mutation manifest a clinical picture of parkinsonism and Lewy Body Dementia, and E46K creates more pathogenic fibrils in vitro. Understanding the effect of these hereditary mutations on α-synuclein fibril structure is fundamental to α-synuclein biology. We therefore determined the cryoEM structure of α-synuclein fibrils containing the hereditary E46K mutation. The 2.5 A structure reveals a symmetric double protofilament in which the molecules adopt a vastly re-arranged, lower energy fold compared to wild-type fibrils. We propose that the E46K misfolding pathway avoids electrostatic repulsion between K46 and K80, a residue pair which forms the E46-K80 salt-bridge in the wild-type fibril structure. We hypothesize that under our conditions the wild-type fold does not reach this deeper energy well of the E46K fold because the E46-K80 salt bridge diverts α-synuclein into a kinetic trap – a shallower, more accessible energy minimum. The E46K mutation apparently unlocks a more stable and pathogenic fibril structure.
53 citations
TL;DR: This study developed an approach that combines the structure-based rational design with chemical modification for the development of amyloid inhibitors, which could be applied to the developed of therapeutics for different amyloids-related diseases.
Abstract: Many human neurodegenerative diseases are associated with amyloid fibril formation. Inhibition of amyloid formation is of importance for therapeutics of the related diseases. However, the development of selective potent amyloid inhibitors remains challenging. Here based on the structures of amyloid β (Aβ) fibrils and their amyloid-forming segments, we designed a series of peptide inhibitors using RosettaDesign. We further utilized a chemical scaffold to constrain the designed peptides into β-strand conformation, which significantly improves the potency of the inhibitors against Aβ aggregation and toxicity. Furthermore, we show that by targeting different Aβ segments, the designed peptide inhibitors can selectively recognize different species of Aβ. Our study developed an approach that combines the structure-based rational design with chemical modification for the development of amyloid inhibitors, which could be applied to the development of therapeutics for different amyloid-related diseases.
48 citations
TL;DR: This work reports the 1.0 Å resolution micro-electron diffraction structure of an aggregation-prone segment of tau with the sequence SVQIVY, present in the cores of patient-derived fibrils from AD and tauopathies, and shows that tau-capping inhibitors can be transiently expressed in HEK293 tau biosensor cells, indicating that nucleic acid–based vectors can be used for inhibitor delivery.
48 citations
TL;DR: These structures suggest that the enhanced amyloidogenicity of the modified Aβ segments may also reduce the concentration required to achieve nucleation and therefore help spur the pathogenesis of AD.
Abstract: Amyloid-β (Aβ) harbors numerous posttranslational modifications (PTMs) that may affect Alzheimer's disease (AD) pathogenesis. Here we present the 1.1 A resolution MicroED structure of an Aβ 20-34 fibril with and without the disease-associated PTM, L-isoaspartate, at position 23 (L-isoAsp23). Both wild-type and L-isoAsp23 protofilaments adopt β-helix-like folds with tightly packed cores, resembling the cores of full-length fibrillar Aβ structures, and both self-associate through two distinct interfaces. One of these is a unique Aβ interface strengthened by the isoaspartyl modification. Powder diffraction patterns suggest a similar structure may be adopted by protofilaments of an analogous segment containing the heritable Iowa mutation, Asp23Asn. Consistent with its early onset phenotype in patients, Asp23Asn accelerates aggregation of Aβ 20-34, as does the L-isoAsp23 modification. These structures suggest that the enhanced amyloidogenicity of the modified Aβ segments may also reduce the concentration required to achieve nucleation and therefore help spur the pathogenesis of AD.
42 citations
TL;DR: Digital biomarkers have potential to improve treatment outcomes in a digital behavioural intervention and were used to transform data from a digital therapeutic into digital biomarkers that predicted treatment response in individual participants.
Abstract: Objectives Development of digital biomarkers to predict treatment response to a digital behavioural intervention. Design Machine learning using random forest classifiers on data generated through the use of a digital therapeutic which delivers behavioural therapy to treat cardiometabolic disease. Data from 13 explanatory variables (biometric and engagement in nature) generated in the first 28 days of a 12-week intervention were used to train models. Two levels of response to treatment were predicted: (1) systolic change ≥10 mm Hg (SC model), and (2) shift down to a blood pressure category of elevated or better (ER model). Models were validated using leave-one-out cross validation and evaluated using area under the curve receiver operating characteristics (AUROC) and specificity- sensitivity. Ability to predict treatment response with a subset of nine variables, including app use and baseline blood pressure, was also tested (models SC-APP and ER-APP). Setting Data generated through ad libitum use of a digital therapeutic in the USA. Participants Deidentified data from 135 adults with a starting blood pressure ≥130/80, who tracked blood pressure for at least 7 weeks using the digital therapeutic. Results The SC model had an AUROC of 0.82 and a sensitivity of 58% at a specificity of 90%. The ER model had an AUROC of 0.69 and a sensitivity of 32% at a specificity at 91%. Dropping explanatory variables related to blood pressure resulted in an AUROC of 0.72 with a sensitivity of 42% at a specificity of 90% for the SC-APP model and an AUROC of 0.53 for the ER-APP model. Conclusions Machine learning was used to transform data from a digital therapeutic into digital biomarkers that predicted treatment response in individual participants. Digital biomarkers have potential to improve treatment outcomes in a digital behavioural intervention.
27 citations
TL;DR: It is found that chemical or mutational stabilization of the transthyretin tetramer does not hinder amyloid seeding, and this findings point to inhibition of amyloids seeding by peptide inhibitors as a potential therapeutic approach.
TL;DR: These study findings suggest that a TK curriculum is feasible within a workplace setting and that its impact on relevant behavioral and clinical outcomes can be scientifically assessed.
Abstract: Objective. To examine the feasibility of a prototype Teaching Kitchen (TK) self-care intervention that offers the combination of culinary, nutrition, exercise, and mindfulness instruction with heal...
TL;DR: In this paper, the effect of doping on carbide-carbon composites was studied and it was shown that doping enhanced activity by nanostructural effects rather than purely catalytic effects, as revealed by electrochemical and material investigations.
Abstract: To expand the range of hydrazine oxidation catalysts active in alkaline pH – a key challenge in fuel cell electrocatalysis – we studied the effect of doping on carbide–carbon composites. Pyrolysis of organometallic precursors based on Fe–M cores (M = Fe/Zn/Cu) yielded Fe3C-embedded, N-doped, hierarchically porous, graphitic carbons. These multi-doped materials showed excellent hydrazine oxidation activity (onset 0.28 V vs. RHE at pH = 14). Doping enhanced activity by nanostructural effects, rather than purely catalytic effects, as revealed by electrochemical and material investigations (XRD, XPS, SEM, TEM, Raman and N2 porosimetry). Zinc and copper boosted microporosity in the carbons by two different mechanisms – either gas phase etching by Zn(g) vapors, or enhanced exfoliation of well-dispersed Cu(s) nanoparticles upon reaction with acid.
12 Mar 2019
TL;DR: Reductions in blood pressure were observed in adults with hypertension who used the digital therapeutic and a successful proof of concept for using machine learning to predict intervention completion was presented.
Abstract: Background: Behavioral therapies, such as electronic counseling and self-monitoring dispensed through mobile apps, have been shown to improve blood pressure, but the results vary and long-term engagement is a challenge. Machine learning is a rapidly advancing discipline that can be used to generate predictive and responsive models for the management and treatment of chronic conditions and shows potential for meaningfully improving outcomes. Objective: The objectives of this retrospective analysis were to examine the effect of a novel digital therapeutic on blood pressure in adults with hypertension and to explore the ability of machine learning to predict participant completion of the intervention. Methods: Participants with hypertension, who engaged with the digital intervention for at least 2 weeks and had paired blood pressure values, were identified from the intervention database. Participants were required to be ≥18 years old, reside in the United States, and own a smartphone. The digital intervention offers personalized behavior therapy, including goal setting, skill building, and self-monitoring. Participants reported blood pressure values at will, and changes were calculated using averages of baseline and final values for each participant. Machine learning was used to generate a model of participants who would complete the intervention. Random forest models were trained at days 1, 3, and 7 of the intervention, and the generalizability of the models was assessed using leave-one-out cross-validation. Results: The primary cohort comprised 172 participants with hypertension, having paired blood pressure values, who were engaged with the intervention. Of the total, 86.1% participants were women, the mean age was 55.0 years (95% CI 53.7-56.2), baseline systolic blood pressure was 138.9 mmHg (95% CI 136.6-141.3), and diastolic was 86.2 mmHg (95% CI 84.8-87.7). Mean change was –11.5 mmHg for systolic blood pressure and –5.9 mmHg for diastolic blood pressure over a mean of 62.6 days (P<.001). Among participants with stage 2 hypertension, mean change was –17.6 mmHg for systolic blood pressure and –8.8 mmHg for diastolic blood pressure. Changes in blood pressure remained significant in a mixed-effects model accounting for the baseline systolic blood pressure, age, gender, and body mass index (P<.001). A total of 43% of the participants tracking their blood pressure at 12 weeks achieved the 2017 American College of Cardiology/American Heart Association definition of blood pressure control. The 7-day predictive model for intervention completion was trained on 427 participants, and the area under the receiver operating characteristic curve was .78. Conclusions: Reductions in blood pressure were observed in adults with hypertension who used the digital therapeutic. The degree of blood pressure reduction was clinically meaningful and achieved rapidly by a majority of the studied participants. Greater improvement was observed in participants with more severe hypertension at baseline. A successful proof of concept for using machine learning to predict intervention completion was presented.
TL;DR: The crystal structure of the EspG1 chaperone from the ESX-1 system determined using a fusion strategy with T4 lysozyme is reported, which adopts a quasi 2-fold symmetric structure that consists of a central β-sheet and two α-helical bundles.
TL;DR: This exploratory study concluded that different food types of similar macronutrient content (e.g., rice and pasta) generate significantly different postprandial glycemic responses in persons with T1D.
Abstract: Background: Food choices are essential to successful glycemic control for people with diabetes. We compared the impact of three carbohydrate-rich meals on the postprandial glycemic respons...
TL;DR: Polyamide and DNA characteristics are combined to form mechanically rigid self-assembled peptide nucleic acid based materials with high stiffness and Young’s modulus, suggesting that the unique cation-free “basket” formed by the Fmoc-G-PNA conjugate can serve as an attractive component for the design of new materials based on PNA self-assembly for nanotechnology applications.
Abstract: The variety and complexity of DNA-based structures make them attractive candidates for nanotechnology, yet insufficient stability and mechanical rigidity, compared to polyamide-based molecules, limit their application. Here, we combine the advantages of polyamide materials and the structural patterns inspired by nucleic-acids to generate a mechanically rigid fluorenylmethyloxycarbonyl (Fmoc)-guanine peptide nucleic acid (PNA) conjugate with diverse morphology and photoluminescent properties. The assembly possesses a unique atomic structure, with each guanine head of one molecule hydrogen bonded to the Fmoc carbonyl tail of another molecule, generating a non-planar cyclic quartet arrangement. This structure exhibits an average stiffness of 69.6 ± 6.8 N m−1 and Young’s modulus of 17.8 ± 2.5 GPa, higher than any previously reported nucleic acid derived structure. This data suggests that the unique cation-free “basket” formed by the Fmoc-G-PNA conjugate can serve as an attractive component for the design of new materials based on PNA self-assembly for nanotechnology applications. DNA is an attractive nanomaterial, yet limited compared to polyamides due to low stability and mechanical issues. Here, the authors combine polyamide and DNA characteristics to form mechanically rigid self-assembled peptide nucleic acid based materials with high stiffness and Young’s modulus.
TL;DR: The identified binding sites of Ab and LilrB2 led to brain-penetrating inhibitors that block Ab-LilRB2 interaction and rescue Ab-induced cytotoxicity, which highlights the therapeutic values of these drug candidates for treating Alzheimer’s disease.
Abstract: Background: Inhibiting the interaction between ß-amyloid (Aß) and a neuronal cell surface receptor, LilrB2, have been suggested as potential route for treating Alzheimer’s disease (AD). Supporting this approach, AD-like symptoms are reduced in mouse models following genetic depletion of the LilrB2 homolog. In its pathogenic, oligomeric state, Aß binds to LilrB2, triggering a pathway to synaptic loss. Methods: To identify suitable therapeutic targets for designing new drugs to inhibit Aß toxicity for Alzheimer’s diseases, we integrated structural, computational, and cellular approaches to elucidate the underlying mechanisms. Results: Here we identified the LilrB2 binding moieties of Aß (KLVFFA) and identified its binding site on LilrB2 from a crystal structure of LilrB2 immunoglobulin domains D1D2 complexed to small molecules that mimic phenylalanine residues. In this structure, we observed two pockets that can accommodate the phenylalanine sidechains of KLVFFA. These pockets were confirmed to be KLVFFA binding sites by mutagenesis. Rosetta docking revealed a plausible geometry for the Aß-LilrB2 complex and assisted with the structure-guided selection of small molecule inhibitors. These molecules inhibit Aß-LilrB2 interactions in vitro and on the cell surface and reduce Aß cytotoxicity, which suggests these inhibitors are potential therapeutic leads against AD. Conclusions: The identified binding sites of Ab and LilrB2 led to brain-penetrating inhibitors that block Ab-LilrB2 interaction and rescue Ab-induced cytotoxicity, which highlights the therapeutic values of these drug candidates for treating Alzheimer’s disease.
TL;DR: Observational prospective cohort study comparing effectiveness and cost-effectiveness of CLBP care provided at an integrative care clinic with that provided in other clinics within the same hospital found trends toward decreased direct expenditures and medication usage over time warrant further investigation.
Abstract: Objectives: To report the results of health economic analyses comparing two treatment approaches for chronic low back pain (CLBP). Design: Observational prospective cohort study comparing ...
TL;DR: The cryo-EM structures of α-synuclein fibrils containing the H50Q hereditary mutation help to rationalize the faster aggregation kinetics, higher seeding capacity in biosensor cells, and greater cytotoxicity the authors observe for H 50Q compared to wild-type α- synuclein.
Abstract: Deposits of amyloid fibrils of alpha synuclein are the histological hallmarks of Parkinsons disease, multiple system atrophy, and dementia with Lewy bodies. Although most cases of these diseases are sporadic, autosomal dominant hereditary mutations have been linked to Parkinsons disease and dementia with Lewy bodies. Seeing the changes to the structure of amyloid fibrils bearing these mutations may help to understand these diseases. To this end, we determined the cryoEM structures of alpha synuclein fibrils containing the H50Q hereditary mutation. We find that the H50Q mutation results in two new polymorphs of alpha synuclein, which we term Narrow and Wide Fibrils. Both polymorphs recapitulate the conserved kernel formed by residues 50 to 77 observed in wild type structures; however, the Narrow and Wide Fibrils reveal that H50Q disrupts a key interaction between H50 and E57 on the opposing protofilament, abolishing the extensive protofilament interface formed by preNAC residues in the wild type rod structure. Instead, the Narrow Fibril is formed from a single protofilament and the two protofilaments of the Wide protofilament are held together by only a pair of atoms, the C gamma atoms from the two threonine 59 sidechains. Further, we find that H50Q forms an intramolecular hydrogen bond with K45 leading to the formation of a novel beta arch formed by residues 36 to 46 that features an extensive hydrogen bond network between Y39, T44, and E46. The structures of the H50Q polymorphs help to rationalize the faster aggregation kinetics, higher seeding capacity in biosensor cells, and greater cytotoxicity we observe for H50Q compared to wild type alpha synuclein.
TL;DR: It is indicated that the dissociation of the TTR tetramer, required for its amyloid pathogenesis, is also necessary to prevent cellular toxicity from Aβ oligomers, suggesting that the Aβ binding site of TTR may be hidden in its tetrameric form.
Abstract: The protective effect of transthyretin (TTR) on cellular toxicity of amyloid-beta (Aβ) has been previously reported. TTR is a tetrameric carrier of thyroxine in blood and cerebrospinal fluid, whose pathogenic aggregation causes systemic amyloidosis. In contrast, many reports have shown that TTR binds amyloid-beta (Aβ), associated with Alzheimer’s disease, alters its aggregation, and inhibits its toxicity both in vitro and in vivo. In this study, we question whether TTR amyloidogenic ability and its anti-amyloid inhibitory effect are associated. Our results indicate that the dissociation of the TTR tetramer, required for its amyloid pathogenesis, is also necessary to prevent cellular toxicity from Aβ oligomers. These findings suggest that the Aβ binding site of TTR may be hidden in its tetrameric form. Aided by computational docking and peptide screening, we identified a TTR segment that is capable of altering Aβ aggregation and toxicity, mimicking TTR cellular protection. This segment inhibits Aβ oligomer formation and also promotes the formation of nontoxic, non-amyloid, amorphous aggregates which are more sensitive to protease digestion. This segment also inhibits seeding of Aβ catalyzed by Aβ fibrils extracted from the brain of an Alzheimer’s patient. Our results suggest that mimicking the inhibitory effect of TTR with peptide-based therapeutics represents an additional avenue to explore for the treatment of Alzheimer’s disease. Significance statement The pathological landmarks of Alzheimer’s disease are the formation of amyloid plaques and neurofibrillary tangles. Amyloid plaques contain fibrous structures made of aggregated amyloid-beta (Aβ). In 1982, Shirahama and colleagues observed the presence of transthyretin (TTR) in these plaques. TTR is a tetrameric protein whose aggregation causes transthyretin amyloidosis. However, TTR protects Aβ from aggregating and causing toxicity to neurons. In this study, we show that the dissociation of TTR tetramers is required to inhibit cellular toxicity caused by Aβ. In addition, we identified a minimum segment of TTR that inhibits Aβ aggregation and cellular toxicity by the formation of amorphous aggregates that are sensitive to proteases, similar to the natural effect of TTR found by others in vivo.
TL;DR: A structure-based model of the binding of the wet interface of the RQEFEV structure with the 313VDLSKVTSKC322 region of the Alzheimer’s Disease tau fibrils structures helps illuminate the possible mechanism of interaction between these two segments, distant in sequence.
Abstract: Although portions of tau protein within the microtubule binding region have been shown to form the ordered core of tau filaments, the structural details of how other regions of tau participate in filament formation are so far unknown. In an attempt to understand how the N-terminus of tau may interact with fibril core, we crystallized and determined the structure of the N-terminal segment 5RQEFEV10 of tau. Several lines of evidence have shown the importance of this segment for fibril formation. The crystal structure reveals an out-of-register Class 5 steric zipper with a wet and a dry interface. To examine the possible interaction of 5RQEFEV10 with the tau fibril core, we modeled the binding of the wet interface of the 5RQEFEV10 structure with the 313VDLSKVTSKC322 region of the Alzheimer’s Disease tau filament structures. This model is consistent with, and helps to explain previous findings on the possible interaction of these two segments, distant in sequence. In addition, we discuss the possible conservation of this interaction across multiple polymorphs of tau.
TL;DR: It is shown that levels of total and misfolded p53 and protein aggregation as identified by Proteostat positivity were MDM2 inhibitors dose- and time-dependent in wt p53 AML cells, and this supports the hypothesis thatMDM2 inhibition can cause not only p53 misfolding but also aggregation.
12 Apr 2019
TL;DR: In this paper, the tetrameric protein transthyretin is a transporter of retinol and thyroxine in blood, cerebrospinal fluid, and the eye, and secreted by the liver, choroid plexus, and retinal epithelium, respectively.
Abstract: The tetrameric protein transthyretin is a transporter of retinol and thyroxine in blood, cerebrospinal fluid, and the eye, and is secreted by the liver, choroid plexus, and retinal epithelium, respectively. Systemic amyloid deposition of aggregated transthyretin causes hereditary and sporadic amyloidoses. A common treatment of patients with hereditary transthyretin amyloidosis is liver transplantation. However, this procedure, which replaces the patient's variant transthyretin with the WT protein, can fail to stop subsequent cardiac deposition, ultimately requiring heart transplantation. We recently showed that preformed amyloid fibrils present in the heart at the time of surgery can template or seed further amyloid aggregation of native transthyretin. Here we assess possible interventions to halt this seeding, using biochemical and EM assays. We found that chemical or mutational stabilization of the transthyretin tetramer does not hinder amyloid seeding. In contrast, binding of the peptide inhibitor TabFH2 to ex vivo fibrils efficiently inhibits amyloid seeding by impeding self-association of the amyloid-driving strands F and H in a tissue-independent manner. Our findings point to inhibition of amyloid seeding by peptide inhibitors as a potential therapeutic approach.
TL;DR: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Patent•
08 Aug 2019TL;DR: In this article, inhibitory peptides which bind to α-synuclein molecules and inhibit α-Synuclein amyloidogenic aggregation and spread of α-Synthesis are described.
Abstract: This invention relates to inhibitory peptides which bind to α-synuclein molecules and inhibit α-synuclein amyloidogenic aggregation, α-synuclein cytotoxicity, and spread of α-synuclein. Methods of making and using the inhibitory peptides (e.g. to treat subjects having conditions or diseases that are mediated by α-synuclein, such as Parkinson's disease, dementia with Lewy bodies, or MSA) are described.