
Jody M MasonUniversity of Bath | UB · Department of Biology and Biochemistry
Jody M Mason
BSc, PhD
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91
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Introduction
Additional affiliations
November 2018 - present
February 2015 - October 2018
October 2007 - January 2015
Publications
Publications (91)
Tauopathies are characterised by the pathological accumulation of misfolded tau. The emerging view is that toxic tau species drive synaptic dysfunction and potentially tau propagation before measurable neurodegeneration is evident, but the underlying molecular events are not well defined. Human non-mutated 0N4R tau (tau WT) and P301L mutant 0N4R ta...
Activating transcription factor 3 (ATF3) is an activation transcription factor/cyclic adenosine monophosphate (cAMP) responsive element-binding (CREB) protein family member. It is recognized as an important regulator of cancer progression by repressing expression of key inflammatory factors such as interferon-γ and chemokine (C–C motif) ligand 4 (C...
Transcription factor dysregulation is associated with many diseases, including cancer. Peptide‐based molecules are increasingly recognised as important modulators of difficult intracellular protein–protein interaction targets, with peptide library screening consequently proven to be a viable strategy in developing inhibitors against a wide range of...
Peptide backbone cyclization is commonly observed in nature and is increasingly applied to proteins and peptides to improve thermal and chemical stability and resistance to proteolytic enzymes and enhance biological activity. However, chemical synthesis of head-to-tail cyclic peptides and proteins is challenging, is often low yielding, and employs...
Peptides and their mimetics are increasingly recognised as drug-like molecules, particularly for intracellular protein-protein interactions too large for inhibition by small molecules, and inaccessible to larger biologics. In the past two decades, evidence associating the misfolding and aggregation of alpha-synuclein strongly implicates this protei...
Parkinson’s is the second most common neurodegenerative disease, with the number of individuals susceptible due to increase as a result of increasing life expectancy and a growing worldwide population. However, despite the number of individuals affected, all current treatments for PD are symptomatic—they alleviate symptoms, but do not slow disease...
Lactate dehydrogenase 5 (LDH5) is overexpressed in many cancers and is a potential target for anticancer therapy due to its role in aerobic glycolysis. Small-molecule drugs have been developed as competitive inhibitors to bind substrate/cofactor sites of LDH5, but none reached the clinic to date. Recently, we designed the first LDH5 non-competitive...
Inhibition of cJun is established as a promising therapeutic approach, particularly in cancer. We recently developed the “transcription block survival” (TBS) screening platform to derive functional peptide antagonists of transcription factor activity by ablating their ability to bind to cognate DNA. Using TBS, we screened a >131,000-member peptide...
α-synuclein (αS) is the key component of synucleinopathies that include Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA). αS was first linked to PD through the identification of point mutations in the SNCA gene, causing single amino acid substitutions within αS and familial autosomal dominant forms of PD...
CCAAT/Enhancer Binding Protein β (C/EBPβ) is a basic leucine zipper (bZIP) family transcription factor that is upregulated or overactivated in many cancers, resulting in gene transactivation that drives oncogenesis. C/EBPβ dimerization regulates binding to DNA at the canonical TTGCGCAA motif and subsequent transcriptional activity, suggesting that...
The AP-1 transcription factor family crucially regulates progression of the cell cycle, as well as playing roles in proliferation, differentiation, and the stress response. The two best described AP-1 family members, cFos and cJun, are known to dimerize to form a functional AP-1 heterodimer that binds to a consensus response element sequence. Altho...
Parkinson's Disease (PD) is characterized by the accumulation of Lewy bodies in dopaminergic neurons. The main protein component of Lewy bodies, α-synuclein (αS), is also firmly linked to PD through the identification of a number of single point mutations that are autosomal dominant for early-onset disease. Consequently, the misfolding and subseque...
We report the development of a high-throughput, intracellular "transcription block survival" (TBS) screening platform to derive functional transcription factor antagonists. TBS is demonstrated using the oncogenic transcriptional regulator cJun, with the development of antagonists that bind cJun and prevent both dimerization and, more importantly, D...
It is now over 30 years since Demchenko and Ladokhin first posited the potential of the tryptophan red edge excitation shift (REES) effect to capture information on protein molecular dynamics. While there have been many key efforts in the intervening years, a biophysical thermodynamic model to quantify the relationship between the REES effect and p...
Misfolding and aggregation of alpha-synuclein (αS) within dopaminergic neurons is a key factor in the development and progression of a group of age-related neurodegenerative diseases, termed synucleinopathies, that include Parkinson's disease (PD). We previously derived a peptide inhibitor from a 209,952-member intracellular library screen by emplo...
It is now over thirty years since Demchenko and Ladokhin first posited the potential of the tryptophan red edge excitation shift (REES) effect to capture information on protein molecular dynamics. Whilst there have been many key efforts in the intervening years, a biophysical thermodynamic model to quantify the relationship between the REES effect...
Aggregation of the microtubule-associated protein tau into paired helical filaments (PHFs) and neurofibrillary tangles is a defining characteristic of Alzheimer’s Disease. Various plant polyphenols disrupt tau aggregation in vitro but display poor bioavailability and low potency, challenging their therapeutic translation. We previously reported tha...
Lactate dehydrogenase 5 (LDH5) is overexpressed in metastatic tumors and is an attractive target for anticancer therapy. Small-molecule drugs have been developed to target the substrate/cofactor sites of LDH5, but none has reached the clinic to date, and alternative strategies remain almost unexplored. Combining rational and computer-based approach...
To date, most research into the inhibition of oncogenic transcriptional regulator, Activator Protein 1 (AP-1), has focused on heterodimers of cJun and cFos. However, the Fra1 homologue remains an important cancer target. Here we describe library design coupled with computational and intracellular screening as an effective methodology to derive an a...
c-Myc is a transcription factor that is constitutively and aberrantly expressed in over 70% of human cancers. Its direct inhibition has been shown to trigger rapid tumor regression in mice with only mild and fully reversible side effects, suggesting this to be a viable therapeutic strategy. Here we reassess the challenges of directly targeting c-My...
Aggregation of α-Synuclein (αS) is widely regarded as a key factor in neuronal cell death, leading to a wide range of synucleinopathies, including Parkinson’s Disease. Development of therapeutics has therefore focused on inhibiting aggregation of αS into toxic forms. One such inhibitor, based on the preNAC region αS45-54 (4554W), was identified usi...
α-Synuclein (aSyn) aggregation is an attractive target for therapeutic development for a range of neurodegenerative conditions, collectively termed synucleinopathies. Here, we probe the mechanism of action of a peptide 4554W, (KDGIVNGVKA), previously identified through intracellular library screening, to prevent aSyn aggregation and associated toxi...
The activator protein-1 (AP-1) family of transcription factors modulate a diverse range of cellular signalling pathways into outputs which can be oncogenic or anti-oncogenic. The transcription of relevant genes is controlled by the cellular context, and in particular by the dimeric composition of AP-1. Here, we describe the evidence linking cJun in...
p>Transcription factor dysregulation is often key to oncogenesis and cancer progression. Direct inhibition of transcription factors provides a logical therapeutic strategy but the broad and shallow interaction interfaces of their protein-protein and protein-DNA interactions are challenging to target using traditional small-molecule approaches. The...
α-Synuclein (αS) deposition is a defining characteristic of Parkinson’s disease (PD) pathology, and other synucleinopathies. αS aggregates in disease, leading to the generation of neuronal inclusions known as Lewy bodies. These accumulate in the cytoplasmic space of dopaminergic neurons in the substantia nigra pars compacta region of the brain, cau...
Correction for ‘Twists or turns: stabilising alpha vs. beta turns in tetrapeptides’ by Huy N. Hoang et al. , Chem. Sci. , 2019, 10 , 10595–10600, DOI: 10.1039/C9SC04153B.
AP-1 proteins are members of the basic leucine zipper (bZIP) protein family of dimeric transcription factors, responsible for controlling many integral cellular processes. These proteins form dimers with each other, and their aberrant expression can lead to a number of cancer types. The oncogenic transcription factor AP-1 binds its target TRE site...
Basic leucine-zipper (bZIP) proteins represent difficult yet compelling oncogenic targets, since numerous cell-signalling cascades converge upon them where they function to modulate transcription of specific gene targets. bZIPs are widely recognised as important regulators of cellular processes that including cell proliferation, apoptosis and cell...
Alpha-synuclein (αS) is the major constituent of Lewy bodies and a pathogenic hallmark of all synucleinopathathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). All diseases are determined by αS aggregate deposition but can be separated into distinct pathological phenotypes and diagnostic c...
Protein-protein interactions involve hotspots as small as 4 sequential amino acids. Corresponding tetrapeptides have no structure in water. Here we report that linking side chains of amino acids X and Z to form 24 cyclic tetrapeptides, cyclo-[XAAZ]-NH2, stabilises 14-18 membered rings that mimic different kinds of non-regular secondary structures f...
There is now crucial medical importance placed on understanding the role of early-stage, sub-visible protein aggregation, particularly in neurodegenerative disease. While there are strategies for detecting such aggregates in vitro, there is no ap-proach at present that can detect these toxic species associated with cells and specific subcellular co...
We have combined two peptide library-screening systems, exploiting the benefits offered by both to select novel antagonistic agents of cJun. CIS display is an in vitro cell-free system that allows very large libraries (≤10(14)) to be interrogated. However, affinity-based screening conditions can poorly reflect those relevant to therapeutic applicat...
The oncogenic transcription factor activator protein-1 (AP-1) is a DNA-binding protein that assembles through dimerization of Fos and Jun protein subunits, their leucine-rich helical sequences entwining into a coiled-coil structure. This study reports on downsizing the proto-oncogene cFos protein (380 residues) to shorter peptides (37–25 residues)...
α-syn is a cytosolic protein known for its association with neurodegenerative diseases that include Parkinson's disease and other synucleinopathies. The potential cellular function of α-synuclein may be of consequence for understanding the pathogenesis of such diseases. Previous work has suggested that α-synuclein can catalyse the reduction of iron...
A major biochemical goal is the ability to mimic nature in engineering highly specific protein-protein interactions. We previously devised a computational interactome screen to identify eight peptides that form four heterospecific dimers despite 32 off-targets. To expand the speed and utility of our approach and the PPI toolkit, we have developed n...
Correction for 'Downsizing the BAD BH3 peptide to small constrained α-helices with improved ligand efficiency' by Nicholas E. Shepherd et al., Org. Biomol. Chem., 2016, DOI: 10.1039/c6ob02185a.
Bcl2 Homology (BH) proteins can either trigger or prevent programmed cell death or apoptosis. Deregulation of the BH protein family network leads to evasion of apoptosis, uncontrolled proliferation and is a hallmark of cancer. Inhibition of pro-survival BH proteins is a promising chemotherapeutic strategy for certain cancers. We have examined wheth...
Helical wheel diagrams for all thirty six possible pairs within the selected eight-peptide interactome. Shown are (a) hypothetical pairs formed by peptide 1-4, (b) hypothetical pairs formed by peptide 5-8 and (c) hypothetical (undesirable) interactions formed between peptides 1-4 and 5-8. Electrostatic attractions and repulsions are shown via blue...
Scatter diagrams for predicted versus observed thermal melting values. Overall the correlation is poor (black line fitted to all 36 data points; r2 = 0.26). The correlation between peptides 5 and 8 is also poor (blue line fitted to 10 blue data points; r2 = 0.29); however, the correlation between peptides 1 and 4 is very good (red line fitted to 10...
Supplementary material
Interactions between naturally occurring proteins are highly specific, with protein-network imbalances associated with numerous diseases. For designed protein-protein interactions (PPIs), required specificity can be notoriously difficult to engineer. To accelerate this process we have derived peptides that form heterospecific PPIs when combined. Th...
Aggregation of α-synuclein (α-syn) into toxic fibrils is a pathogenic hallmark of Parkinson's disease (PD). Studies have largely focused on residues 71-82, yet most early onset mutations are located between residues 46-53. A semi-rationally designed 209,952 member library library based entirely on this region was constructed, containing all wild-ty...
In the modern age of proteomics, vast numbers of protein-protein interactions (PPIs) are being identified as causative agents in pathogenesis, and are thus attractive therapeutic targets for intervention. Although traditionally regarded unfavorably as druggable agents relative to small molecules, peptides in recent years have gained considerable at...
The β-amyloid (Aβ) peptide aggregates into a number of soluble and insoluble forms, with soluble oligomers thought to be the primary factor implicated in Alzheimer's disease (AD) pathology. As a result, a wide range of potential aggregation inhibitors have been developed. However, in addition to problems with solubility and protease susceptibility,...
The aggregation of β-amyloid (Aβ) into toxic oligomers is a hallmark of Alzheimer´s disease pathology. Here we present a novel approach for the development of peptides capable of preventing amyloid aggregation based upon the previous selection of natural all-L peptides that bind Aβ1-42. Using an intracellular selection system, successful library me...
Aggregation of the β-amyloid (Aβ) peptide into toxic oligomers is considered the primary event in the pathogenesis of Alzheimer's
disease. Previously generated peptides and mimetics designed to bind to amyloid fibrils have encountered problems in solubility,
protease susceptibility and the population of small soluble toxic oligomers. We present a n...
Protein-based therapeutics feature large interacting surfaces. Protein folding endows structural stability to localised surface epitopes, imparting high affinity and target specificity upon interactions with binding partners. However, short synthetic peptides with sequences corresponding to such protein epitopes are unstructured in water and promis...
Raw thermal melting data for homo and heterodimeric complexes with cJun for constrained peptides 1, 2, 8, 9, 10, 11, 12, 17, 20, 22, and 24. Shown are raw thermal melting data for all homo and heterodimeric complexes. Data have been collected by measuring the level of helicity at 222 nm in an applied photophysics chirascan Circular Dichroism (CD) S...
CD spectra as MRE both in isolation and as a mixture with cJun. From these raw data it is also clear that no interaction is occurring between constrained peptides and cJun. Rather, specta appear as averages of their homodimeric components (i.e. superimpose with the homomeric averages). We observe no heteromeric helical signal (red) that exceeds the...
Assigned 1H NMR signals for peptide 24 in H2O:D2O (9∶1) at 298
K.
(DOC)
CD spectra for all constraints in this study. These are shown both in isolation and as a mixture with cFos. Data have been collected by measuring the level of helicity at 222 nm in an applied photophysics chirascan Circular Dichroism (CD) Spectrometer. Data have been converted from raw ellipticity to Molar Residue Ellipticity (MRE). From these raw...
Dimer exchange experiments between cJun, cFos and constrained peptide 24.
a) Equimolar mixures of cJun-cJun and cFos-24 are mixed and the observed signal closely resembles the average of the two constituent spectra, indicating no change has occurred. b) Equimolar mixtures of cFos-cFos and cJun-24 are mixed and the observed spectra greatly exceeds t...
Supporting Information.
(DOC)
Helical Data obtained via Circular Dichroism. Shown are A) homo and B) heteromeric samples. Column 1 displays the 222/208 ratio which can be used as an indication of the presence of coiled coils. A ratio higher than 1 is generally indicated evidence that a coiled coil has formed, while a ratio of less than 0.9 is taken to indicate the presence of i...
The DNA binding activity of the transcriptional regulator activator protein-1 shows considerable promise as a target in cancer
therapy. A number of different strategies have been employed to inhibit the function of this protein with promise having been
demonstrated both in vitro and in vivo. Peptide-based therapeutics have received renewed interest...
The DNA binding activity of the transcriptional regulator activator protein-1 shows considerable promise as a target in cancer therapy. A number of different strategies have been employed to inhibit the function of this protein with promise having been demonstrated both in vitro and in vivo. Peptide-based therapeutics have received renewed interest...
Dimerization of the Jun–Fos activator protein-1 (AP-1) transcriptional regulator is mediated by coiled coil regions that facilitate binding of the basic regions to a specific promoter. AP-1 is responsible for the regulation of a number of genes involved in cell proliferation. We have previously derived peptide antagonists and demonstrated them to b...
The concept of peptides as therapeutic agents has been historically disregarded by the pharmaceutical industry on account of their susceptibility to degradation, their size and consequent limitations in methods of delivery. Recently, however, there has been a surge of interest in peptides and their mimetics as potential antagonists for therapeutic...
The hypothesis is tested that Jun-Fos activator protein-1 coiled coil interactions are dominated during late folding events by the formation of intricate intermolecular electrostatic contacts. A previously derived cJun-FosW was used as a template as it is a highly stable relative of the wild-type cJun-cFos coiled coil protein (thermal melting tempe...
We have screened two coiled coil-forming libraries in which core a and electrostatic e/g positions have been partially randomized. We observed the relative ability of these residues to confer coiled coil stability using a protein-fragment complementation assay. Our studies continue with the Jun/Fos activator protein-1 (AP-1) leucine zipper complex,...
We have employed semirational design in combination with selection systems to generate peptides interfering with a pathogenic protein-protein interaction: the transcriptional regulator Activator Protein-1 (AP-1). Peptide inhibitors with high interaction stability were screened and selected using either phage display or protein-fragment complementat...
Semi-rational design is combined with PCAs (protein-fragment complementation assays) and phage-display screening techniques to generate a range of iPEPs (interfering peptides) that target therapeutically relevant proteins with much higher interaction stability than their native complexes. PCA selection has been improved to impose a competitive and...
The activator protein-1 (AP-1) complex plays a crucial role in numerous pathways, and its ability to induce tumorigenesis is well documented. Thus, AP-1 represents an interesting therapeutic target. We selected peptides from phage display and compared their ability to disrupt the cFos/cJun interaction to a previously described in vivo protein-fragm...
Relating primary sequence to three-dimensional structure has long been the holy grail of structural biology and appears to be far from achievement. Within grasp however, is the use of intuitive or unintuitive methodology to modify existing known protein structures to achieve the desired effect. We use protein engineering as a general term for the d...
Two c-Jun leucine zipper variants that bind with high affinity to c-Fos have been selected using semirational design combined
with protein-fragment complementation assays (JunW) or phage display selection (JunWPh1). Enriched winners differ from each other in only two of ten semi-randomized positions, with ΔTm values of 28 °C and 37 °C over wild-typ...
The energetic determinants that drive specific protein-protein interactions are not entirely understood. We describe simultaneous in vivo selection of specific and stable interactions using homologous peptides which compete with protein libraries for an interaction with a target molecule. Library members binding to their target, and promoting cell...
Coiled coil motifs are, despite their apparent simplicity, highly specific, and play a significant role in the understanding of tertiary structure and its formation. The most commonly observed of the coiled coils, the parallel dimeric, is yet to be fully characterized for this structural class in general. Nonetheless, strict rules have emerged for...
Improving enzyme stability is a highly desirable design step in generating enzymes able to function under extreme conditions, such as elevated temperatures, while having the additional benefit of being less susceptible to cleavage by proteases. For these reasons, many different approaches and techniques have been devised in constructing such protei...