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3 results on '"Poepsel S"'

1. Determinants of structural and functional plasticity of a widely conserved protease chaperone complex.

Author

Merdanovic M, Mamant N, Meltzer M, Poepsel S, Auckenthaler A, Melgaard R, Hauske P, Nagel-Steger L, Clarke AR, Kaiser M, Huber R, and Ehrmann M

Subjects
Amino Acid Sequence, Bacteria genetics, Bacterial Proteins genetics, Catalytic Domain, Heat-Shock Proteins genetics, Models, Molecular, PDZ Domains, Peptides chemistry, Peptides metabolism, Periplasmic Proteins genetics, Point Mutation, Protein Binding, Protein Folding, Protein Multimerization, Serine Endopeptidases genetics, Bacteria metabolism, Bacterial Proteins chemistry, Bacterial Proteins metabolism, Heat-Shock Proteins chemistry, Heat-Shock Proteins metabolism, Periplasmic Proteins chemistry, Periplasmic Proteins metabolism, Serine Endopeptidases chemistry, Serine Endopeptidases metabolism
Abstract

Channeling of misfolded proteins into repair, assembly or degradation pathways is often mediated by complex and multifunctional cellular factors. Despite detailed structural information, the underlying regulatory mechanisms governing these factors are not well understood. The extracytoplasmic heat-shock factor DegP (HtrA) is a well-suited model for addressing mechanistic issues, as it is regulated by the common mechanisms of allostery and activation by oligomerization. Site-directed mutagenesis combined with refolding and oligomerization studies of chemically denatured DegP revealed how substrates trigger the conversion of the resting conformation into the active conformation. Binding of specific peptides to PDZ domain-1 causes a local rearrangement that is allosterically transmitted to the substrate-binding pocket of the protease domain. This activated state readily assembles into larger oligomeric particles, thus stabilizing the catalytically active form and providing a degradation cavity for protein substrates. The implications of these data for the mechanism of protein quality control are discussed.

Published
2010
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2. Structure, function and regulation of the conserved serine proteases DegP and DegS of Escherichia coli.

Author

Meltzer M, Hasenbein S, Mamant N, Merdanovic M, Poepsel S, Hauske P, Kaiser M, Huber R, Krojer T, Clausen T, and Ehrmann M

Subjects
Escherichia coli genetics, Gene Expression Regulation, Bacterial, Escherichia coli enzymology, Escherichia coli Proteins chemistry, Escherichia coli Proteins metabolism, Heat-Shock Proteins chemistry, Heat-Shock Proteins metabolism, Periplasmic Proteins chemistry, Periplasmic Proteins metabolism, Serine Endopeptidases chemistry, Serine Endopeptidases metabolism
Abstract

Two members of the widely conserved HtrA family of serine proteases, DegP and DegS, are key players in extracytoplasmic protein quality control. The underlying mechanisms of their main functions in stress sensing, regulation and protection during the unfolded protein response are discussed.

Published
2009
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3. Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition

Author

Winkler, R., Mägdefrau, A.S., Piskor, E.M., Kleemann, M., Beyer, M., Linke, K., Hansen, L., Schaffer, A.M., Hoffmann, M.E., Poepsel, S., Heyd, F., Beli, P., Möröy, T., Mahboobi, S., Krämer, O.H., Kosan, C., and Universitat Autònoma de Barcelona

Subjects
Cancer Research, Lymphoma, B-Cell, MYC interaction network, Histone Deacetylase 6, Histone Deacetylases, Mice, Tubulin, Genetics, medicine, Animals, Humans, B-cell lymphoma, Molecular Biology, Heat-Shock Proteins, Chemistry, Cancer, Acetylation, Oncogenes, 500 Naturwissenschaften und Mathematik::570 Biowissenschaften, Biologie::570 Biowissenschaften, Biologie, HDAC6, HSP40 Heat-Shock Proteins, medicine.disease, Lymphoma, Histone Deacetylase Inhibitors, Apoptosis, Cancer cell, Cancer research, DNAJA3, Transcription Factors
Abstract

RW was supported by a scholarship from the Carl Zeiss Foundation. CK received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), GRK 1715. E-MP was supported by a Landesgraduiertenstipendium (Friedrich Schiller University Jena). Work done in the group of OHK was done by MB and is funded by DFG, Project-ID 393547839-SFB 1361 and DFG, GRK 2291/9-1, project number 427404172. Open Access funding enabled and organized by Projekt DEAL. Overexpression of MYC is a genuine cancer driver in lymphomas and related to poor prognosis. However, therapeutic targeting of the transcription factor MYC remains challenging. Here, we show that inhibition of the histone deacetylase 6 (HDAC6) using the HDAC6 inhibitor Marbostat-100 (M-100) reduces oncogenic MYC levels and prevents lymphomagenesis in a mouse model of MYC-induced aggressive B-cell lymphoma. M-100 specifically alters protein-protein interactions by switching the acetylation state of HDAC6 substrates, such as tubulin. Tubulin facilitates nuclear import of MYC, and MYC-dependent B-cell lymphoma cells rely on continuous import of MYC due to its high turn-over. Acetylation of tubulin impairs this mechanism and enables proteasomal degradation of MYC. M-100 targets almost exclusively B-cell lymphoma cells with high levels of MYC whereas non-tumor cells are not affected. M-100 induces massive apoptosis in human and murine MYC-overexpressing B-cell lymphoma cells. We identified the heat-shock protein DNAJA3 as an interactor of tubulin in an acetylation-dependent manner and overexpression of DNAJA3 resulted in a pronounced degradation of MYC. We propose a mechanism by which DNAJA3 associates with hyperacetylated tubulin in the cytoplasm to control MYC turnover. Taken together, our data demonstrate a beneficial role of HDAC6 inhibition in MYC-dependent B-cell lymphoma.

Published
2022

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