Jinghui Luo

Paul Scherrer Institut | PSI · Laboratory of Biomolecular Research

The coacervation and structural rearrangement of the protein alpha-synuclein (αSyn) into cytotoxic oligomers and amyloid fibrils are considered pathological hallmarks of Parkinson's disease. While aggregation is recognized as the key element of amyloid diseases, liquid-liquid phase separation (LLPS) and its interplay with aggregation have gained in...

Background Abnormal alpha-synuclein and iron accumulation in the brain play an important role in Parkinson’s disease (PD). Herein, we aim at visualizing alpha-synuclein inclusions and iron deposition in the brains of M83 (A53T) mouse models of PD in vivo . Methods Fluorescently labelled pyrimidoindole-derivative THK-565 was characterized by using...

Oligomerization of antimicrobial peptides (AMPs) is critical in their effects on pathogens. LL‐37 and its truncated fragments are widely investigated regarding their structures, antimicrobial activities, and application, such as developing new antibiotics. Due to the small size and weak intermolecular interactions of LL‐37 fragments, it is still el...

Prevalent in nature, protein oligomers play critical roles both physiologically and pathologically. The multimeric nature and conformational transiency of protein oligomers greatly complicate a more detailed glimpse into the molecular structure as well as function. In this minireview, the oligomers are classified and described on the basis of biolo...

Prevalently in nature, protein oligomers play critical roles both physiologically and pathologically. The multimeric nature and conformational transiency of protein oligomers greatly complicate a more detailed glimpse into the molecular structure as well as function. In this minireview, the oligomers are classified and elaborated on the basis of bi...

Three common Apolipoprotein E isoforms, ApoE2, ApoE3, and ApoE4, are key regulators of lipid homeostasis, among other functions. Apolipoprotein E can interact with amyloid proteins. The isoforms differ by one or two residues at positions 112 and 158, and possess distinct structural conformations and functions, leading to isoform-specific roles in a...

Amyloid-β (Aβ) peptide aggregation plays a central role in the progress of Alzheimer’s disease (AD), of which Aβ-deposited extracellular amyloid plaques are a major hallmark. The brain micro-environmental variation in AD patients, like local acidification, increased ionic strength, or changed metal ion levels, cooperatively modulates the aggregatio...

Protein homeostasis collapse typically leads to protein aggregation into amyloid fibrils and diffuse amorphous aggregates, which both occur in Alzheimer’s and other neurodegenerative diseases, but their relationship remains to be clarified. Here we examine the interactions between the amorphously aggregated non-chaperone proteins (albumin, β-lactog...

α-synuclein protein aggregates are the major constituent of Lewy bodies, which is a main pathogenic hallmark of Parkinson's disease. Both lipid membranes and Cu²⁺ ions can bind to α-synuclein and modulate its aggregation propensity and toxicity. However, the synergistic effect of copper ions and lipid membranes on α-synuclein remains to be explored...

The tight binding of Cu and Zn ions to superoxide dismutase 1 (SOD1) maintains the protein stability, associated with amyotrophic lateral sclerosis (ALS). Yet, the quantitative studies remain to be explored for the metal-binding affinity of wild-type SOD1 and its mutants. We have investigated the demetallation of Cu,Zn-SOD1 and its ALS-related G93A...

Misfolding of the human protein α-synuclein results in toxic fibrils and the aggregation of Lewy bodies, which are a hallmark of Parkinson's disease in brain tissue. Here we disclose a supramolecular approach where peptidomimetics are rationally designed and pre-organised to recognize the surface of native helical α-Syn by forming complementary con...

The lipid-α-Synuclein (α-Syn) interaction plays a crucial role in the pathogenesis of Parkinson's disease. Here, we trap α-Syn at conjunction of an α-hemolysin (αHL) single nanopore-lipid to investigate the folding and unfolding kinetics of α-Syn in a lipidic environment. The hybridized α-Syn is generated through a reaction between a 5′-thiol-modif...

Prion disease is a fatal neurodegenerative disorder, in which the cellular prion protein PrPC is converted to a misfolded prion which in turn is hypothesized to permeabilize cellular membranes. The pathways leading to toxicity in prion disease are not yet completely elucidated and whether it also includes formation of membrane pores remains to be a...

Heat shock protein 90 (Hsp90) is a molecular chaperone that assists protein folding in an Adenosine triphosphate (ATP)-dependent way. Hsp90 has been reported to interact with Alzheimeŕs disease associated amyloid-β (Aβ) peptides and to suppress toxic oligomer- and fibril formation. However, the mechanism remains largely unclear. Here we use a combi...

We study the interaction between the Aβ peptides and Cu and Zn metal ions by using soft X-ray absorption spectroscopy. The spectral features of the peptides and the Cu are simultaneously characterized by recording spectra at the N K edge and at the Cu L2,3 edges. In the presence of the peptides, the Cu L2,3 edge shows a fingerprint of monovalent Cu...

Amyloid‐β peptide (Aβ) oligomers are pathogenic species of amyloid aggregates in Alzheimer's disease. Like certain protein toxins, Aβ oligomers permeabilize cellular membranes, presumably through a pore formation mechanism. Owing to their structural and stoichiometric heterogeneity, the structure of these pores remains to be characterized. We studi...

A functional and structural Aβ42-oligomer equivalent, created by fusing Aβ42 to the oligomerizing, soluble domain of the α-hemolysin (αHL) toxin, share major structural, functional, and biological properties with Alzheimer's wild-type Aβ42 oligomers. Cryo-EM studies reveal that the αHL-displayed oligomers structurally remain a well-defined stoichio...

Heat shock protein 90 (Hsp90) is a molecular chaperone that assists protein folding in an Adenosine triphosphate (ATP)-dependent way. Hsp90 has been reported to interact with Alzheimeŕs disease associated amyloid-β (Aβ) peptides and to suppress toxic oligomer- and fibril formation. However, the mechanism remains largely unclear. Here we use a combi...

In neurodegenerative diseases, a wide range of amyloid proteins or peptides such as amyloid-beta and α -synuclein fail to keep native functional conformations, followed by misfolding and self-assembling into a diverse array of aggregates. The aggregates further exert toxicity leading to the dysfunction, degeneration and loss of cells in the affecte...

Mimics of natural antimicrobial peptides are promising compounds to fight the rising threat of multi‐drug resistant bacteria. Here we report the design, synthesis and conformational analysis of a new class of antimicrobial peptide mimetics incorporating a diphenylacetylene scaffold. Within a small set of compounds, we observe a correlation between...

The amyloid-β (Aβ) peptides are key molecules in Alzheimer’s disease (AD) pathology. They interact with cellular membranes, and can bind metal ions outside the membrane. Certain oligomeric Aβ aggregates are known to induce membrane perturbations and the structure of these oligomers—and their membrane-perturbing effects—can be modulated by metal ion...

Large multi-protein nanopores remain difficult to reconstitute in vitro, such as for instance the nuclear pore complex (NPC) that regulates macromolecular transport between the nucleus and cytoplasm in cells. Here, we report that two NPC pore membrane proteins self-assemble into ~20 nm-diameter nanopores following in vitro reconstitution into lipid...

In Alzheimer’s disease, amyloid-β (Aβ) plaques and tau neurofibrillary tangles are the two pathological hallmarks. The co-occurrence and combined reciprocal pathological effects of Aβ and tau protein aggregation have been observed in animal models of the disease. However, the molecular mechanism of their interaction remain unknown. Using a variety...

Cigarette smoking is a significant risk factor for Alzheimer's disease (AD), which is associated with extracellular brain deposits of amyloid plaques containing aggregated amyloid-β (Aβ) peptides. Aβ aggregation occurs via multiple pathways that can be influenced by various compounds. Here, we used AFM imaging and NMR, fluorescence, and mass spectr...

Albumin is the most abundant plasma protein and as such has been the subject of many studies using a variety of techniques. One of them, capable of monitoring the conformational changes and the binding capacity of proteins, is electron paramagnetic resonance spectroscopy (EPR) spin labeling. To date, albumin has been investigated using a number of...

This review describes interactions between the amyloid-β peptide (Aβ) involved in Alzheimer's disease (AD) and endogenous metal ions and proteins, with an emphasis on future potential drug therapies and targets. AD is characterised by loss of neurons, memory, and cognitive functions, and by formation of cerebral senile plaque deposits. These plaque...

Aggregation of the amyloid-beta (Aβ) peptide into insoluble plaques is a major factor in Alzheimer's disease (AD) pathology. Another major factor in AD is arguably metal ions, as metal dyshomeostasis is observed in AD patients, metal ions modulate Aβ aggregation, and AD plaques contain numerous metals including redox-active Cu and Fe ions. In vivo,...

Conformationally-constrained molecules that selectively recognise the surfaces of proteins have the potential to direct the path of protein folding. Such molecules are of therapeutic interest because the misfolding of proteins, especially that which results in fibrillation and aggregation, is strongly correlated with numerous diseases. Here we repo...

Many protein folding diseases are intimately associated with accumulation of amyloid aggregates. The amyloid materials formed by different proteins/peptides share many struxctural similarities, despite sometimes large amino acid sequence differences. Some amyloid diseases constitute risk factors for others, and the progression of one amyloid diseas...

Clinical studies indicate Diabetes Mellitus type II (DM) doubles the risk that a patient will also develop Alzheimer´s disease (AD). DM is caused by insulin resistance and a relative lack of active insulin. AD is characterised by the deposition of amyloid β (Aβ) peptide fibrils. Prior to fibrillating, Aβ forms intermediate, pre-fibrillar oligomers,...

Protein/peptide oligomerisation, cross-β strand fibrillation and amyloid deposition play a critical role in many diseases1-4 but despite extensive biophysical characterization5-7, the structural and dynamic details of oligomerisation and fibrillation of amyloidic peptides/proteins remain to be fully clarified8. Here, we simultaneously monitored the...

Many factors are known to influence the oligomerization, fibrillation, and amyloid formation of the Aβ peptide that is associated with Alzheimer disease. Other proteins that are present when Aβ peptides deposit in vivo are likely to have an effect on these aggregation processes. To separate specific versus broad spectrum effects of proteins on Aβ a...

Many neurodegenerative diseases, like Parkin-son's, Alzheimer's, or Huntington's disease, occur as a result of amyloid protein fibril formation and cell death induced by this process. Cyclic peptides (CPs) and their derivatives form a new class of powerful inhibitors that prevent amyloid fibrillation and decrease the cytotoxicity of aggregates. The...

Carbon nanotubes have specific properties that make them potentially useful in biomedicine and biotechnology. However, carbon nanotubes may themselves be toxic, making it imperative to understand how carbon nanotubes interact with biomolecules such as proteins. Here, we used NMR, CD, and ThT/fluorescence spectroscopy together with AFM imaging to st...

Polyamines promote the formation of the A-beta peptide amyloid fibers that are a hallmark of Alzheimer's Disease. Here we show that polyamines interact with non-aggregated A-beta peptides, thereby reducing the peptide's hydrophobic surface. We characterized the associated conformational change through NMR titrations and molecular dynamics simulatio...

The amyloid β (Aβ) peptides are 39-42 residue-long peptides found in the senile plaques in the brains of Alzheimer's disease (AD) patients. These peptides self-aggregate in aqueous solution, going from soluble and mainly unstructured monomers to insoluble ordered fibrils. The aggregation process(es) are strongly influenced by environmental conditio...

Many neurodegenerative diseases, like Parkinson's, Alzheimer's, or Huntington's disease, occur as a result of amyloid protein fibril formation and cell death induced by this process. Cyclic peptides (CPs) and their derivatives form a new class of powerful inhibitors that prevent amyloid fibrillation and decrease the cytotoxicity of aggregates. The...

In Alzheimer's disease, amyloid-β (Aβ) peptides aggregate into extracellular fibrillar deposits. Although these deposits may not be the prime cause of the neurodegeneration that characterizes this disease, inhibition or dissolution of amyloid fibril formation by Aβ peptides is likely to affect its development. ThT fluorescence measurements and AFM...

Alzheimer's disease is the most common of the protein misfolding ("amyloid") diseases. The deposits in the brains of afflicted patients contain as a major fraction an aggregated insoluble form of the so-called amyloid β-peptides (Aβ peptides): fragments of the amyloid precursor protein of 39-43 residues in length. This review focuses on biophysical...

Alzheimer's disease is a neurodegenerative disorder characterized by accumulation of Aβ peptide aggregates in the brain. Using ThT fluorescence assays, AFM imaging, NMR and CD spectroscopy, and MD modeling we show that lysozyme - a hydrolytic enzyme abundant in human secretions - completely inhibits the aggregation of Aβ peptides at equimolar lysoz...

The crystal structures of various important membrane proteins could not have been solved without lipidic cubic phase (LCP) crystallization, and yet, compared to traditional in surfo crystallization, LCP crystallization is not widely used because its extreme viscosity makes the cubic phase difficult to handle. Robots that can dispense LCPs are very...

Knowing the molecular details of the interaction between riboswitch aptamers and their corresponding metabolites is important to understand gene expression. Here we report on a novel in vitro assay to study preQ1 riboswitch aptamers upon binding of 7-aminomethyl-7-deazaguanine (preQ1). The assay is based on the ability of the preQ1 aptamer to fold,...

Single-stranded DNA (ssDNA) is characterized by high conformational flexibility that allows these molecules to adopt a variety of conformations. Here we used native polyacrylamide gel electrophoresis (PAGE), circular dichroism (CD) spectroscopy and nuclear magnetic resonance (NMR) spectroscopy to show that cytosine methylation at CpG sites affects...

Melting temperature (Tm), number of G-C, A-T, and G-T base pairs, and folding energies (ΔG) between 5 and 37°C for seven different secondary structures of the Dyn A-coding sequence. (DOC)

In recent years, it has become increasingly clear that many enzymes are catalytically "promiscuous". This can provide a springboard for protein evolution, allowing enzymes to acquire novel functionality without compromising their native activities. We present here a detailed study of Pseudomonas aeruginosa arylsulfatase (PAS), which catalyzes the h...

Pseudomonas aeruginosa arylsulfatase (PAS) is a bacterial sulfatase capable of hydrolyzing a range of sulfate esters. Recently, it has been demonstrated to also show very high proficiency for phosphate ester hydrolysis. Such proficient catalytic promiscuity is significant, as promiscuity has been suggested to play an important role in enzyme evolut...

Chlamydia trachomatis ribonucleotide reductase (RNR) is a class Ic RNR. It has two homodimeric subunits: proteins R1 and R2. Class Ic protein R2 in its most active form has a manganese-iron metal cofactor, which functions in catalysis like the tyrosyl radical in classical class Ia and Ib RNRs. Oligopeptides with the same sequence as the C-terminus...

Ribonucleotide reductase (RNR) is necessary for production of the precursor deoxyribonucleotides for DNA synthesis. Class Ia RNR functions via a stable free radical in one of the two components protein R2. The enzyme mechanism involves long range (proton coupled) electron transfer between protein R1 and the tyrosyl radical in protein R2. Earlier ex...

Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone, 3-AP) is currently the most promising chemotherapeutic compound among the class of α-N-heterocyclic thiosemicarbazones. Here we report further insights into the mechanism(s) of anticancer drug activity and inhibition of mouse ribonucleotide reductase (RNR) by Triapine. In addition to the...

Growing X-ray grade crystals of a specific protein is a process of trial and error. Usually, hundreds or even thousands of conditions are screened in order to identify useful crystallization conditions. Heterogeneous nucleants have been shown to increase the success rate of crystallization trials, and (human) hair has previously been identified as...

The relationship between Apolipoprotein E (ApoE) and the aggregation processes of the amyloid beta (A beta) peptide has been shown to be crucial for Alzheimer's disease (AD). The presence of the ApoE4 isoform is considered to be a contributing risk factor for AD. However, the detailed molecular properties of ApoE4 interacting with the A beta peptid...

The relationship between Apolipoprotein E (ApoE) and the aggregation processes of the amyloid β (Aβ) peptide has been shown to be crucial for Alzheimer's disease (AD). ApoE4 is considered as a contributing risk factor for AD. Although various mechanisms have been proposed to explain the physiological and pathological role of this relationship, the...

Iron is an important factor for cell growth, and cell proliferation can be inhibited due to lack of iron. Ribonucleotide reductase (RNR), a bottleneck enzyme for synthesis of the precursor deoxyribonucleotides for DNA synthesis, requires iron for activity. Certain studies have shown that iron chelators can be used as potential agents against tumor...