Zweckstetter, Markus

[["dc.bibliographiccitation.firstpage","1545"],["dc.bibliographiccitation.issue","28"],["dc.bibliographiccitation.journal","Protein Science"],["dc.bibliographiccitation.lastpage","1551"],["dc.contributor.author","Oroz, Javier"],["dc.contributor.author","Blair, Laura J."],["dc.contributor.author","Zweckstetter, Markus"],["dc.date.accessioned","2019-11-27T13:35:15Z"],["dc.date.accessioned","2021-10-27T13:21:38Z"],["dc.date.available","2019-11-27T13:35:15Z"],["dc.date.available","2021-10-27T13:21:38Z"],["dc.date.issued","2019"],["dc.description.abstract","Hsp90 is an essential chaperone that requires large allosteric changes to determine its ATPase activity and client binding. The co-chaperone Aha1, which is the major ATPase stimulator in eukaryotes, is important for regulation of Hsp90's allosteric timing. Little is known, however, about the structure of the Hsp90/Aha1 complex. Here, we characterize the solution structure of unmodified human Hsp90/Aha1 complex using NMR spectroscopy. We show that the 214-kDa complex forms by a two-step binding mechanism and adopts multiple conformations in the absence of nucleotide. Aha1 induces structural changes near Hsp90's nucleotide-binding site, providing a basis for its ATPase-enhancing activity. Our data reveal important aspects of this pivotal chaperone/co-chaperone interaction and emphasize the relevance of characterizing dynamic chaperone structures in solution."],["dc.identifier.doi","10.1002/pro.3678"],["dc.identifier.isbn","31299134"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16757"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/92037"],["dc.language.iso","en"],["dc.notes.intern","Migrated from goescholar"],["dc.relation.eissn","1469-896X"],["dc.relation.issn","1469-896X"],["dc.relation.issn","0961-8368"],["dc.relation.orgunit","Universitätsmedizin Göttingen"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","Dynamic Aha1 co‐chaperone binding to human Hsp90"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","6503"],["dc.bibliographiccitation.issue","26"],["dc.bibliographiccitation.journal","Chemical Science"],["dc.bibliographiccitation.lastpage","6507"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Ambadipudi, Susmitha"],["dc.contributor.author","Reddy, Jithender G."],["dc.contributor.author","Biernat, Jacek"],["dc.contributor.author","Mandelkow, Eckhard"],["dc.contributor.author","Zweckstetter, Markus"],["dc.date.accessioned","2019-09-30T09:26:49Z"],["dc.date.accessioned","2021-10-27T13:21:20Z"],["dc.date.available","2019-09-30T09:26:49Z"],["dc.date.available","2021-10-27T13:21:20Z"],["dc.date.issued","2019"],["dc.description.abstract","Liquid-liquid phase separation (LLPS) of proteins enables the formation of non-membrane-bound organelles in cells and is associated with cancer and neurodegeneration. Little is known however about the structure and dynamics of proteins in LLPS conditions, because of the polymorphic nature of liquid-like protein droplets. Using carbon-detected NMR experiments we here show that the conversion of the aggregation-prone repeat region of the Alzheimer's-related protein tau from the dispersed monomeric state to phase-separated liquid-like droplets involves tau's aggregation-prone hexapeptides and regulatory KXGS motifs. Droplet dissolution in presence of 1,6-hexanediol revealed that chemical shift perturbations in the hexapeptide motifs are temperature driven, while those in KXGS motifs report on phase separation. Residue-specific secondary structure analysis further indicated that tau's repeat region exists in extended conformation in the dispersed state and attains transient β-hairpin propensity upon LLPS. Taken together our work shows that NMR spectroscopy can provide high-resolution insights into LLPS-induced changes in intrinsically disordered proteins."],["dc.identifier.doi","10.1039/C9SC00531E"],["dc.identifier.pmid","31341602"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16419"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/92013"],["dc.language.iso","en"],["dc.notes.intern","Migrated from goescholar"],["dc.relation.eissn","2041-6539"],["dc.relation.issn","2041-6520"],["dc.relation.orgunit","Universitätsmedizin Göttingen"],["dc.rights","CC BY-NC 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc/3.0"],["dc.subject.ddc","610"],["dc.title","Residue-specific identification of phase separation hot spots of Alzheimer's-related protein tau"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","4532"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Nature Communications"],["dc.bibliographiccitation.volume","9"],["dc.contributor.author","Oroz, Javier"],["dc.contributor.author","Chang, Bliss J."],["dc.contributor.author","Wysoczanski, Piotr"],["dc.contributor.author","Lee, Chung-Tien"],["dc.contributor.author","Pérez-Lara, Ángel"],["dc.contributor.author","Chakraborty, Pijush"],["dc.contributor.author","Hofele, Romina V."],["dc.contributor.author","Baker, Jeremy D."],["dc.contributor.author","Blair, Laura J."],["dc.contributor.author","Biernat, Jacek"],["dc.contributor.author","Urlaub, Henning"],["dc.contributor.author","Mandelkow, Eckhard"],["dc.contributor.author","Dickey, Chad A."],["dc.contributor.author","Zweckstetter, Markus"],["dc.date.accessioned","2019-07-09T11:50:23Z"],["dc.date.available","2019-07-09T11:50:23Z"],["dc.date.issued","2018"],["dc.description.abstract","The molecular chaperone Hsp90 is critical for the maintenance of cellular homeostasis and represents a promising drug target. Despite increasing knowledge on the structure of Hsp90, the molecular basis of substrate recognition and pro-folding by Hsp90/co-chaperone complexes remains unknown. Here, we report the solution structures of human full-length Hsp90 in complex with the PPIase FKBP51, as well as the 280 kDa Hsp90/FKBP51 complex bound to the Alzheimer's disease-related protein Tau. We reveal that the FKBP51/Hsp90 complex, which synergizes to promote toxic Tau oligomers in vivo, is highly dynamic and stabilizes the extended conformation of the Hsp90 dimer resulting in decreased Hsp90 ATPase activity. Within the ternary Hsp90/FKBP51/Tau complex, Hsp90 serves as a scaffold that traps the PPIase and nucleates multiple conformations of Tau's proline-rich region next to the PPIase catalytic pocket in a phosphorylation-dependent manner. Our study defines a conceptual model for dynamic Hsp90/co-chaperone/client recognition."],["dc.identifier.doi","10.1038/s41467-018-06880-0"],["dc.identifier.pmid","30382094"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15928"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59763"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation","info:eu-repo/grantAgreement/EC/FP7/626526/EU//HSP70-TAU NMR"],["dc.relation","info:eu-repo/grantAgreement/EC/FP7/283570/EU//BIOSTRUCT-X"],["dc.relation.issn","2041-1723"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","Structure and pro-toxic mechanism of the human Hsp90/PPIase/Tau complex"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","49"],["dc.bibliographiccitation.journal","Frontiers in Molecular Neuroscience"],["dc.bibliographiccitation.volume","11"],["dc.contributor.author","Tolö, Johan"],["dc.contributor.author","Taschenberger, Grit"],["dc.contributor.author","Leite, Kristian"],["dc.contributor.author","Stahlberg, Markus A."],["dc.contributor.author","Spehlbrink, Gesche"],["dc.contributor.author","Kues, Janina"],["dc.contributor.author","Munari, Francesca"],["dc.contributor.author","Capaldi, Stefano"],["dc.contributor.author","Becker, Stefan"],["dc.contributor.author","Zweckstetter, Markus"],["dc.contributor.author","Dean, Camin"],["dc.contributor.author","Bähr, Mathias"],["dc.contributor.author","Kügler, Sebastian"],["dc.date.accessioned","2019-07-09T11:45:10Z"],["dc.date.available","2019-07-09T11:45:10Z"],["dc.date.issued","2018"],["dc.description.abstract","α-Synuclein (α-Syn) is intimately linked to the etiology of Parkinson's Disease, as mutations and even subtle increases in gene dosage result in early onset of the disease. However, how this protein causes neuronal dysfunction and neurodegeneration is incompletely understood. We thus examined a comprehensive range of physiological parameters in cultured rat primary neurons overexpressing α-Syn at levels causing a slowly progressive neurodegeneration. In contradiction to earlier reports from non-neuronal assay systems we demonstrate that α-Syn does not interfere with essential ion handling capacities, mitochondrial capability of ATP production or basic electro-physiological properties like resting membrane potential or the general ability to generate action potentials. α-Syn also does not activate canonical stress kinase Signaling converging on SAPK/Jun, p38 MAPK or Erk kinases. Causative for α-Syn-induced neurodegeneration are mitochondrial thiol oxidation and activation of caspases downstream of mitochondrial outer membrane permeabilization, leading to apoptosis-like cell death execution with some unusual aspects. We also aimed to elucidate neuroprotective strategies counteracting the pathophysiological processes caused by α-Syn. Neurotrophic factors, calpain inhibition and increased lysosomal protease capacity showed no protective effects against α-Syn overexpression. In contrast, the major watchdog of outer mitochondrial membrane integrity, Bcl-Xl, was capable of almost completely preventing neuron death, but did not prevent mitochondrial thiol oxidation. Importantly, independent from the quite mono-causal induction of neurotoxicity, α-Syn causes diminished excitability of neurons by external stimuli and robust impairments in endogenous neuronal network activity by decreasing the frequency of action potentials generated without external stimulation. This latter finding suggests that α-Syn can induce neuronal dysfunction independent from its induction of neurotoxicity and might serve as an explanation for functional deficits that precede neuronal cell loss in synucleopathies like Parkinson's disease or dementia with Lewy bodies."],["dc.identifier.doi","10.3389/fnmol.2018.00049"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15047"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59171"],["dc.language.iso","en"],["dc.notes.intern","DeepGreen Import"],["dc.publisher","Frontiers Media S.A."],["dc.relation.eissn","1662-5099"],["dc.relation.issn","1662-5099"],["dc.rights","http://creativecommons.org/licenses/by/4.0/"],["dc.subject.ddc","610"],["dc.title","Pathophysiological Consequences of Neuronal α-Synuclein Overexpression: Impacts on Ion Homeostasis, Stress Signaling, Mitochondrial Integrity, and Electrical Activity"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]