Marie-Therese Mackmull


Last Name

Mackmull

First Name

Marie-Therese

ORCID

0000-0003-2928-1144

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Publications1 - 4 of 4
  • Conserved exchange of paralog proteins during neuronal differentiation
    Item type: Journal Article
    Di Fraia, Domenico; Anitei, Mihaela; Mackmull, Marie-Therese; et al. (2022)
    Life Science Alliance
    Gene duplication enables the emergence of new functions by lowering the evolutionary pressure that is posed on the ancestral genes. Previous studies have highlighted the role of specific paralog genes during cell differentiation, for example, in chromatin remodeling complexes. It remains unexplored whether similar mechanisms extend to other biological functions and whether the regulation of paralog genes is conserved across species. Here, we analyze the expression of paralogs across human tissues, during development and neuronal differentiation in fish, rodents and humans. Whereas ∼80% of paralog genes are co-regulated, a subset of paralogs shows divergent expression profiles, contributing to variability of protein complexes. We identify 78 substitutions of paralog pairs that occur during neuronal differentiation and are conserved across species. Among these, we highlight a substitution between the paralogs SEC23A and SEC23B members of the COPII complex. Altering the ratio between these two genes via RNAi-mediated knockdown is sufficient to influence neuron differentiation. We propose that remodeling of the vesicular transport system via paralog substitutions is an evolutionary conserved mechanism enabling neuronal differentiation.
  • Global, in situ analysis of the structural proteome in individuals with Parkinson's disease to identify a new class of biomarker
    Item type: Journal Article
    Mackmull, Marie-Therese; Nagel, Luise; Sesterhenn, Fabian; et al. (2022)
    Nature Structural & Molecular Biology
    Parkinson's disease (PD) is a prevalent neurodegenerative disease for which robust biomarkers are needed. Because protein structure reflects function, we tested whether global, in situ analysis of protein structural changes provides insight into PD pathophysiology and could inform a new concept of structural disease biomarkers. Using limited proteolysis-mass spectrometry (LiP-MS), we identified 76 structurally altered proteins in cerebrospinal fluid (CSF) of individuals with PD relative to healthy donors. These proteins were enriched in processes misregulated in PD, and some proteins also showed structural changes in PD brain samples. CSF protein structural information outperformed abundance information in discriminating between healthy participants and those with PD and improved the discriminatory performance of CSF measures of the hallmark PD protein alpha-synuclein. We also present the first analysis of inter-individual variability of a structural proteome in healthy individuals, identifying biophysical features of variable protein regions. Although independent validation is needed, our data suggest that global analyses of the human structural proteome will guide the development of novel structural biomarkers of disease and enable hypothesis generation about underlying disease processes.
  • Discovering the nuclear localization signal of Werner Helicase Interacting Protein 1
    Item type: Other Journal Item
    Jordan, Benjamin R.; Zhai, Yujia; Li, Zhi; et al. (2023)
    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
    Our study maps the classic nuclear localization signal (cNLS) domain within WRNIP that directs the protein's nuclear positioning.
  • Bioaccumulation of therapeutic drugs by human gut bacteria
    Item type: Journal Article
    Klünemann, Martina; Andrejev, Sergej; Blasche, Sonja; et al. (2021)
    Nature
    Bacteria in the gut can modulate the availability and efficacy of therapeutic drugs. However, the systematic mapping ofthe interactions between drugs and bacteria has only started recently' and the main underlying mechanism proposed is the chemical transformation of drugs by microorganisms (biotransformation). Here we investigated the depletion of 15 structurally diverse drugs by 25 representative strains of gut bacteria. This revealed 70 bacteria-drug interactions, 29 of which had not to our knowledge been reported before. Over half of the new interactions can be ascribed to bioaccumulation; that is, bacteria storing the drug intracellularly without chemically modifying it, and in most cases without the growth ofthe bacteria being affected. As a case in point, we studied the molecular basis of bioaccumulation of the widely used antidepressant duloxetine by using click chemistry, thermal proteome profiling and metabolomics. We find that duloxetine bindsto several metabolic enzymes and changes the metabolite secretion of the respective bacteria. When tested in a defined microbial community of accumulators and non-accumulators, duloxetine markedly altered the composition of the community through metabolic cross-feeding. We further validated our findings in an animal model, showing that bioaccumulating bacteria attenuate the behavioural response of Caenorhabditis elegansto duloxetine. Together, our results show that bioaccumulation by gut bacteria may be a common mechanism that alters drug availability and bacterial metabolism, with implications for microbiota composition, pharmacokinetics, side effects and drug responses, probably in an individual manner. © 2021 Springer Nature Limited
Publications1 - 4 of 4