Zweckstetter, Markus

[["dc.bibliographiccitation.artnumber","e2001336"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","PLoS Biology"],["dc.bibliographiccitation.volume","15"],["dc.contributor.author","Baker, Jeremy D."],["dc.contributor.author","Shelton, Lindsey B."],["dc.contributor.author","Zheng, Dali"],["dc.contributor.author","Favretto, Filippo"],["dc.contributor.author","Nordhues, Bryce A."],["dc.contributor.author","Darling, April"],["dc.contributor.author","Sullivan, Leia E."],["dc.contributor.author","Sun, Zheying"],["dc.contributor.author","Solanki, Parth K."],["dc.contributor.author","Martin, Mackenzie D."],["dc.contributor.author","Suntharalingam, Amirthaa"],["dc.contributor.author","Sabbagh, Jonathan J."],["dc.contributor.author","Becker, Stefan"],["dc.contributor.author","Mandelkow, Eckhard"],["dc.contributor.author","Uversky, Vladimir N."],["dc.contributor.author","Zweckstetter, Markus"],["dc.contributor.author","Dickey, Chad A."],["dc.contributor.author","Koren, John, III"],["dc.contributor.author","Blair, Laura J."],["dc.date.accessioned","2018-11-07T10:22:54Z"],["dc.date.available","2018-11-07T10:22:54Z"],["dc.date.issued","2017"],["dc.description.abstract","The accumulation of amyloidogenic proteins is a pathological hallmark of neurodegenerative disorders. The aberrant accumulation of the microtubule associating protein tau (MAPT, tau) into toxic oligomers and amyloid deposits is a primary pathology in tauopathies, the most common of which is Alzheimer's disease (AD). Intrinsically disordered proteins, like tau, are enriched with proline residues that regulate both secondary structure and aggregation propensity. The orientation of proline residues is regulated by cis/trans peptidyl-prolyl isomerases (PPIases). Here we show that cyclophilin 40 (CyP40), a PPIase, dissolves tau amyloids in vitro. Additionally, CyP40 ameliorated silver-positive and oligomeric tau species in a mouse model of tau accumulation, preserving neuronal health and cognition. Nuclear magnetic resonance (NMR) revealed that CyP40 interacts with tau at sites rich in proline residues. CyP40 was also able to interact with and disaggregate other aggregating proteins that contain prolines. Moreover, CyP40 lacking PPIase activity prevented its capacity for disaggregation in vitro. Finally, we describe a unique structural property of CyP40 that may permit disaggregation to occur in an energy-independent manner. This study identifies a novel human protein disaggregase and, for the first time, demonstrates its capacity to dissolve intracellular amyloids."],["dc.identifier.doi","10.1371/journal.pbio.2001336"],["dc.identifier.isi","000404510400007"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14553"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/42356"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Public Library Science"],["dc.relation.issn","1545-7885"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Human cyclophilin 40 unravels neurotoxic amyloids"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e1000034"],["dc.bibliographiccitation.firstpage","399"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","PLoS Biology"],["dc.bibliographiccitation.lastpage","414"],["dc.bibliographiccitation.volume","7"],["dc.contributor.author","Mukrasch, Marco D."],["dc.contributor.author","Bibow, Stefan"],["dc.contributor.author","Korukottu, Jegannath"],["dc.contributor.author","Jeganathan, Sadasivam"],["dc.contributor.author","Biernat, Jacek"],["dc.contributor.author","Griesinger, Christian"],["dc.contributor.author","Mandelkow, Eckhard"],["dc.contributor.author","Zweckstetter, Markus"],["dc.date.accessioned","2017-09-07T11:47:34Z"],["dc.date.available","2017-09-07T11:47:34Z"],["dc.date.issued","2009"],["dc.description.abstract","Alzheimer disease is characterized by abnormal protein deposits in the brain, such as extracellular amyloid plaques and intracellular neurofibrillary tangles. The tangles are made of a protein called tau comprising 441 residues in its longest isoform. Tau belongs to the class of natively unfolded proteins, binds to and stabilizes microtubules, and partially folds into an ordered beta-structure during aggregation to Alzheimer paired helical filaments (PHFs). Here we show that it is possible to overcome the size limitations that have traditionally hampered detailed nuclear magnetic resonance (NMR) spectroscopy studies of such large nonglobular proteins. This is achieved using optimal NMR pulse sequences and matching of chemical shifts from smaller segments in a divide and conquer strategy. The methodology reveals that 441-residue tau is highly dynamic in solution with a distinct domain character and an intricate network of transient long-range contacts important for pathogenic aggregation. Moreover, the single-residue view provided by the NMR analysis reveals unique insights into the interaction of tau with microtubules. Our results establish that NMR spectroscopy can provide detailed insight into the structural polymorphism of very large nonglobular proteins."],["dc.identifier.doi","10.1371/journal.pbio.1000034"],["dc.identifier.gro","3143159"],["dc.identifier.isi","000263599900018"],["dc.identifier.pmid","19226187"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/8445"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/642"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Public Library Science"],["dc.relation.issn","1544-9173"],["dc.rights","CC BY 2.5"],["dc.rights.uri","https://creativecommons.org/licenses/by/2.5"],["dc.title","Structural Polymorphism of 441-Residue Tau at Single Residue Resolution"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","2909"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Nature Communications"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Ukmar-Godec, Tina"],["dc.contributor.author","Hutten, Saskia"],["dc.contributor.author","Grieshop, Matthew P."],["dc.contributor.author","Rezaei-Ghaleh, Nasrollah"],["dc.contributor.author","Cima-Omori, Maria-Sol"],["dc.contributor.author","Biernat, Jacek"],["dc.contributor.author","Mandelkow, Eckhard"],["dc.contributor.author","Söding, Johannes"],["dc.contributor.author","Dormann, Dorothee"],["dc.contributor.author","Zweckstetter, Markus"],["dc.date.accessioned","2019-07-22T12:49:00Z"],["dc.date.available","2019-07-22T12:49:00Z"],["dc.date.issued","2019-07-02"],["dc.description.abstract","Cells form and use biomolecular condensates to execute biochemical reactions. The molecular properties of non-membrane-bound condensates are directly connected to the amino acid content of disordered protein regions. Lysine plays an important role in cellular function, but little is known about its role in biomolecular condensation. Here we show that protein disorder is abundant in protein/RNA granules and lysine is enriched in disordered regions of proteins in P-bodies compared to the entire human disordered proteome. Lysine-rich polypeptides phase separate into lysine/RNA-coacervates that are more dynamic and differ at the molecular level from arginine/RNA-coacervates. Consistent with the ability of lysine to drive phase separation, lysine-rich variants of the Alzheimer's disease-linked protein tau undergo coacervation with RNA in vitro and bind to stress granules in cells. Acetylation of lysine reverses liquid-liquid phase separation and reduces colocalization of tau with stress granules. Our study establishes lysine as an important regulator of cellular condensation."],["dc.identifier.doi","10.1038/s41467-019-10792-y"],["dc.identifier.pmid","31266957"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16293"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/61798"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.eissn","2041-1723"],["dc.relation.issn","2041-1723"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Lysine/RNA-interactions drive and regulate biomolecular condensation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Nature Communications"],["dc.bibliographiccitation.volume","8"],["dc.contributor.author","Ambadipudi, Susmitha"],["dc.contributor.author","Biernat, Jacek"],["dc.contributor.author","Riedel, Dietmar"],["dc.contributor.author","Mandelkow, Eckhard"],["dc.contributor.author","Zweckstetter, Markus"],["dc.date.accessioned","2019-07-09T11:43:48Z"],["dc.date.available","2019-07-09T11:43:48Z"],["dc.date.issued","2017"],["dc.identifier.doi","10.1038/s41467-017-00480-0"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14684"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/58973"],["dc.notes.intern","Merged from goescholar"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Liquid–liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein Tau"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Nature Communications"],["dc.bibliographiccitation.volume","8"],["dc.contributor.author","Cabrales Fontela, Yunior"],["dc.contributor.author","Kadavath, Harindranath"],["dc.contributor.author","Biernat, Jacek"],["dc.contributor.author","Riedel, Dietmar"],["dc.contributor.author","Mandelkow, Eckhard"],["dc.contributor.author","Zweckstetter, Markus"],["dc.date.accessioned","2020-12-10T18:09:44Z"],["dc.date.available","2020-12-10T18:09:44Z"],["dc.date.issued","2017"],["dc.identifier.doi","10.1038/s41467-017-02230-8"],["dc.identifier.eissn","2041-1723"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16721"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/73745"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.notes.intern","Merged from goescholar"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau"],["dc.type","journal_article"],["dc.type.internalPublication","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"]]