Dataset Information

Meltome Atlas - thermal proteome stability across the tree of life

ABSTRACT: We have developed a mass spectrometry-based approach that allowed us to quantitatively monitor protein stability across a broad range of temperatures at the proteome scale (meltome). We profiled the meltomes of several microorganisms and eukaryotic species including human, allowing to investigate the determinants of protein thermostability and survival in various environmental niches. Moreover, we will make Meltome Atlas a valuable, publicly available resource for the biological community to investigate their proteins of interest in the context of protein thermostbility.

INSTRUMENT(S): Orbitrap Fusion Lumos, Exactive Plus

ORGANISM(S): Thermus Thermophilus (strain Hb8 / Atcc 27634 / Dsm 579) Picrophilus Torridus Oleispira Antarctica Danio Rerio (zebrafish) (brachydanio Rerio) Caenorhabditis Elegans Saccharomyces Cerevisiae (baker's Yeast) Bacillus Subtilis Drosophila Melanogaster (fruit Fly) Homo Sapiens (human) Escherichia Coli Arabidopsis Thaliana (mouse-ear Cress) Geobacillus Stearothermophilus Mus Musculus (mouse)

TISSUE(S): Hepatocyte, Blood Plasma, Seminal Plasma, Liver, Cerebrospinal Fluid, Fibroblast Of Lung, Fibroblast, Saliva, Milk

SUBMITTER: Anna Jarzab

LAB HEAD: Bernhard Kuster

PROVIDER: PXD011929 | Pride | 2020-04-29

REPOSITORIES: Pride

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Publications

Meltome atlas-thermal proteome stability across the tree of life.

Jarzab Anna A Kurzawa Nils N Hopf Thomas T Moerch Matthias M Zecha Jana J Leijten Niels N Bian Yangyang Y Musiol Eva E Maschberger Melanie M Stoehr Gabriele G Becher Isabelle I Daly Charlotte C Samaras Patroklos P Mergner Julia J Spanier Britta B Angelov Angel A Werner Thilo T Bantscheff Marcus M Wilhelm Mathias M Klingenspor Martin M Lemeer Simone S Liebl Wolfgang W Hahne Hannes H Savitski Mikhail M MM Kuster Bernhard B

Nature methods 20200413 5

We have used a mass spectrometry-based proteomic approach to compile an atlas of the thermal stability of 48,000 proteins across 13 species ranging from archaea to humans and covering melting temperatures of 30-90 °C. Protein sequence, composition and size affect thermal stability in prokaryotes and eukaryotic proteins show a nonlinear relationship between the degree of disordered protein structure and thermal stability. The data indicate that evolutionary conservation of protein complexes is re ...[more]

PMID: 32284610

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Project description:Parasitic diseases of humans and other animals represent a major socioeconomic burden worldwide. In humans, parasitic worms (helminths) that cause neglected tropical diseases (NTDs) affect ~ billion people, equating to a burden of >12 million disability-adjusted life years (DALYs) (Hotez et al., 2014). In other animals, although challenging to quantitate, the disease impact of such helminths is major (Pedersen, et al., 2015; Charlier et al., 2020; Selzer and Epe, 2021), and some of these parasites are also transmissible to humans (i.e. zoonotic) (McCarthy et al., 2000; Gordon et al., 2016). The control of these diseases relies on diagnosis, treatment and management strategies, and anthelmintic treatment is usually a central component of a control campaign, as vaccines are not available for the vast majority of them. These treatments are not always highly efficacious/effective, and the reliance on them, particularly if they are used excessively in an uncontrolled (suppressive) manner, has led to the emergence and spread of anthelmintic resistances in parasitic worms (within 4-X generations; REF), particularly those of animals. Although the resistance status of worms of humans to available compounds is somewhat unclear (Prichard, 2005; Keiser and Utzinger, 2008; Vercruysse et al., 2011), this is not the case for worms of important production animals (e.g., sheep, goats and pigs), where such resistance(s) is/are widespread and essentially worldwide. In recent work, we established a high-throughput whole-organism, phenotypic assay for the screening of relatively large libraries of tens to hundreds of thousands of compounds, the subsequent evaluation of active compounds and structure-activity relationship (SAR) studies to strive toward the optimisation of the activity and potency of analogs, and the minimisation of side effects and toxicity (Taki et al., 2021b; Taki et al., 2021c; Shanley et al., 2022). However, our early discovery work has been hampered by not knowing the target(s) to which compounds might bind and how they might work. In recent years, there have been major advances in the development of methods for identifying drug-target interactions (reviewed by Mateus et al., 2021), which include affinity purification, activity-based protein profiling, kinobeads (for kinases), stability of proteins from rates of oxidation, protein painting, limited proteolysis/drug affinity responsive target stability and thermal proteome profiling (TPP). Published evidence (Savitski et al., 2014; Perrin et al., 2020; Selkrig et al., 2020) demonstrates clearly the exquisite capacity of TPP to define or infer target molecules in projects with a biomedical focus (e.g., cancer, autophagy or infectious disease), but this method has not yet been utilised to define an anthelmintic target. This context provides the very exciting prospect of being able to rapidly provide evidence of drug-target interactions. For these reasons, in the present study, we undertook a high-throughput whole-organism, phenotypic screen of a well-curated compound library, identified ‘hit’ compounds for evaluation, identified one candidate with lead-like characteristics and inferred the target of this promising small molecule in H. contortus.

Dataset Information

Meltome Atlas - thermal proteome stability across the tree of life

Publications

Meltome atlas-thermal proteome stability across the tree of life.

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