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Article ; Online: Perfect match: PET ligand fits snugly into folded Tau filaments.

Savastano, Adriana

2023 Volume 30, Issue 6, Page(s) 721

MeSH term(s)	Humans ; Ligands ; Alzheimer Disease ; tau Proteins/metabolism ; Cytoskeleton/metabolism ; Positron-Emission Tomography ; Brain/metabolism
Chemical Substances	Ligands ; tau Proteins
Language	English
Publishing date	2023-06-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2126708-X
ISSN	1545-9985 ; 1545-9993
ISSN (online)	1545-9985
ISSN	1545-9993
DOI	10.1038/s41594-023-01025-4
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Zs.A 4101: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Book ; Online ; Thesis: Investigation on the Physiological and Pathological Aspects of the Proline-Rich Region of the Microtubule-Associated Protein Tau

Savastano, Adriana [Verfasser]

2020

Author's details	Adriana Savastano
Keywords	Biowissenschaften, Biologie ; Life Science, Biology
Subject code	sg570
Language	English
Publisher	Niedersächsische Staats- und Universitätsbibliothek Göttingen
Publishing place	Göttingen
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article ; Online: Contributions of the N-terminal intrinsically disordered region of the severe acute respiratory syndrome coronavirus 2 nucleocapsid protein to RNA-induced phase separation.

Zachrdla, Milan / Savastano, Adriana / Ibáñez de Opakua, Alain / Cima-Omori, Maria-Sol / Zweckstetter, Markus

Protein science : a publication of the Protein Society

2022 Volume 31, Issue 9, Page(s) e4409

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein is an essential structural component of mature virions, encapsulating the genomic RNA and modulating RNA transcription and replication. Several of its activities might be ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein is an essential structural component of mature virions, encapsulating the genomic RNA and modulating RNA transcription and replication. Several of its activities might be associated with the protein's ability to undergo liquid-liquid phase separation. N
MeSH term(s)	COVID-19/genetics ; Humans ; Nucleocapsid Proteins/chemistry ; Nucleocapsid Proteins/genetics ; Nucleocapsid Proteins/metabolism ; RNA, Viral/chemistry ; SARS-CoV-2/genetics
Chemical Substances	Nucleocapsid Proteins ; RNA, Viral
Language	English
Publishing date	2022-08-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1106283-6
ISSN	1469-896X ; 0961-8368
ISSN (online)	1469-896X
ISSN	0961-8368
DOI	10.1002/pro.4409
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Zs.A 3407: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Multivalent Tau/PSD-95 interactions arrest in vitro condensates and clusters mimicking the postsynaptic density.

Shen, Zheng / Sun, Daxiao / Savastano, Adriana / Varga, Sára Joana / Cima-Omori, Maria-Sol / Becker, Stefan / Honigmann, Alf / Zweckstetter, Markus

Nature communications

2023 Volume 14, Issue 1, Page(s) 6839

Abstract: Alzheimer's disease begins with mild memory loss and slowly destroys memory and thinking. Cognitive impairment in Alzheimer's disease has been associated with the localization of the microtubule-associated protein Tau at the postsynapse. However, the ... ...

Abstract	Alzheimer's disease begins with mild memory loss and slowly destroys memory and thinking. Cognitive impairment in Alzheimer's disease has been associated with the localization of the microtubule-associated protein Tau at the postsynapse. However, the correlation between Tau at the postsynapse and synaptic dysfunction remains unclear. Here, we show that Tau arrests liquid-like droplets formed by the four postsynaptic density proteins PSD-95, GKAP, Shank, Homer in solution, as well as NMDA (N-methyl-D-aspartate)-receptor-associated protein clusters on synthetic membranes. Tau-mediated condensate/cluster arrest critically depends on the binding of multiple interaction motifs of Tau to a canonical GMP-binding pocket in the guanylate kinase domain of PSD-95. We further reveal that competitive binding of a high-affinity phosphorylated peptide to PSD-95 rescues the diffusional dynamics of an NMDA truncated construct, which contains the last five amino acids of the NMDA receptor subunit NR2B fused to the C-terminus of the tetrameric GCN4 coiled-coil domain, in postsynaptic density-like condensates/clusters. Taken together, our findings propose a molecular mechanism where Tau modulates the dynamic properties of the postsynaptic density.
MeSH term(s)	Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Nerve Tissue Proteins/metabolism ; Post-Synaptic Density/metabolism ; Alzheimer Disease ; N-Methylaspartate ; Membrane Proteins/metabolism ; Disks Large Homolog 4 Protein/metabolism ; Receptors, N-Methyl-D-Aspartate/metabolism
Chemical Substances	Intracellular Signaling Peptides and Proteins ; Nerve Tissue Proteins ; N-Methylaspartate (6384-92-5) ; Membrane Proteins ; Disks Large Homolog 4 Protein ; Receptors, N-Methyl-D-Aspartate
Language	English
Publishing date	2023-10-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-42295-2
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Article ; Online: Solid-state NMR investigation of the involvement of the P2 region in tau amyloid fibrils.

Savastano, Adriana / Jaipuria, Garima / Andreas, Loren / Mandelkow, Eckhard / Zweckstetter, Markus

Scientific reports

2020 Volume 10, Issue 1, Page(s) 21210

Abstract: The aggregation of hyperphosphorylated tau into amyloid fibrils is closely linked to the progression of Alzheimer's disease. To gain insight into the link between amyloid structure and disease, the three-dimensional structure of tau fibrils has been ... ...

Abstract	The aggregation of hyperphosphorylated tau into amyloid fibrils is closely linked to the progression of Alzheimer's disease. To gain insight into the link between amyloid structure and disease, the three-dimensional structure of tau fibrils has been studied using solid-state NMR (ssNMR) and cryogenic electron microscopy (cryo-EM). The proline-rich region of tau remains poorly defined in the context of tau amyloid structures, despite the clustering of several phosphorylation sites, which have been associated with Alzheimer's disease. In order to gain insight into the contribution of the proline-rich region P2 of tau to amyloid fibrils, we studied in vitro aggregated amyloid fibrils of tau constructs, which contain both the proline-rich region P2 and the pseudo-repeats. Using ssNMR we show that the sequence [Formula: see text], the most hydrophobic patch within the P2 region, loses its flexibility upon formation of amyloid fibrils. The data suggest a contribution of the P2 region to tau amyloid fibril formation, which might account for some of the unassigned electron density in cryo-EM studies of tau fibrils and could be modulated by tau phosphorylation at the disease-associated AT180 epitope T231/S235.
MeSH term(s)	Amyloid/chemistry ; Amyloid/metabolism ; Epitopes/metabolism ; Humans ; Nuclear Magnetic Resonance, Biomolecular/methods ; Phosphorylation ; Protein Conformation ; Protein Domains ; tau Proteins/chemistry ; tau Proteins/metabolism
Chemical Substances	Amyloid ; Epitopes ; MAPT protein, human ; tau Proteins
Language	English
Publishing date	2020-12-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-78161-0
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Article ; Online: Multivalent Tau/PSD-95 interactions arrest in vitro condensates and clusters mimicking the postsynaptic density

Zheng Shen / Daxiao Sun / Adriana Savastano / Sára Joana Varga / Maria-Sol Cima-Omori / Stefan Becker / Alf Honigmann / Markus Zweckstetter

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 13

Abstract: Abstract Alzheimer’s disease begins with mild memory loss and slowly destroys memory and thinking. Cognitive impairment in Alzheimer’s disease has been associated with the localization of the microtubule-associated protein Tau at the postsynapse. However, ...

Abstract	Abstract Alzheimer’s disease begins with mild memory loss and slowly destroys memory and thinking. Cognitive impairment in Alzheimer’s disease has been associated with the localization of the microtubule-associated protein Tau at the postsynapse. However, the correlation between Tau at the postsynapse and synaptic dysfunction remains unclear. Here, we show that Tau arrests liquid-like droplets formed by the four postsynaptic density proteins PSD-95, GKAP, Shank, Homer in solution, as well as NMDA (N-methyl-D-aspartate)-receptor-associated protein clusters on synthetic membranes. Tau-mediated condensate/cluster arrest critically depends on the binding of multiple interaction motifs of Tau to a canonical GMP-binding pocket in the guanylate kinase domain of PSD-95. We further reveal that competitive binding of a high-affinity phosphorylated peptide to PSD-95 rescues the diffusional dynamics of an NMDA truncated construct, which contains the last five amino acids of the NMDA receptor subunit NR2B fused to the C-terminus of the tetrameric GCN4 coiled-coil domain, in postsynaptic density-like condensates/clusters. Taken together, our findings propose a molecular mechanism where Tau modulates the dynamic properties of the postsynaptic density.
Keywords	Science ; Q
Subject code	571
Language	English
Publishing date	2023-10-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Nucleocapsid protein of SARS-CoV-2 phase separates into RNA-rich polymerase-containing condensates.

Savastano, Adriana / Ibáñez de Opakua, Alain / Rankovic, Marija / Zweckstetter, Markus

Nature communications

2020 Volume 11, Issue 1, Page(s) 6041

Abstract: The etiologic agent of the Covid-19 pandemic is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The viral membrane of SARS-CoV-2 surrounds a helical nucleocapsid in which the viral genome is encapsulated by the nucleocapsid protein. The ...

Abstract	The etiologic agent of the Covid-19 pandemic is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The viral membrane of SARS-CoV-2 surrounds a helical nucleocapsid in which the viral genome is encapsulated by the nucleocapsid protein. The nucleocapsid protein of SARS-CoV-2 is produced at high levels within infected cells, enhances the efficiency of viral RNA transcription, and is essential for viral replication. Here, we show that RNA induces cooperative liquid-liquid phase separation of the SARS-CoV-2 nucleocapsid protein. In agreement with its ability to phase separate in vitro, we show that the protein associates in cells with stress granules, cytoplasmic RNA/protein granules that form through liquid-liquid phase separation and are modulated by viruses to maximize replication efficiency. Liquid-liquid phase separation generates high-density protein/RNA condensates that recruit the RNA-dependent RNA polymerase complex of SARS-CoV-2 providing a mechanism for efficient transcription of viral RNA. Inhibition of RNA-induced phase separation of the nucleocapsid protein by small molecules or biologics thus can interfere with a key step in the SARS-CoV-2 replication cycle.
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; COVID-19/epidemiology ; COVID-19/virology ; Coronavirus Nucleocapsid Proteins/antagonists & inhibitors ; Coronavirus Nucleocapsid Proteins/metabolism ; Coronavirus RNA-Dependent RNA Polymerase/metabolism ; HeLa Cells ; Humans ; Insecta ; Intravital Microscopy ; Microscopy, Fluorescence ; Molecular Dynamics Simulation ; Pandemics/prevention & control ; Phosphoproteins/antagonists & inhibitors ; Phosphoproteins/metabolism ; RNA, Viral/antagonists & inhibitors ; RNA, Viral/metabolism ; SARS-CoV-2/drug effects ; SARS-CoV-2/physiology ; Viral Transcription/drug effects ; Viral Transcription/physiology ; Virus Replication/drug effects ; Virus Replication/genetics ; COVID-19 Drug Treatment
Chemical Substances	Antiviral Agents ; Coronavirus Nucleocapsid Proteins ; Phosphoproteins ; RNA, Viral ; nucleocapsid phosphoprotein, SARS-CoV-2 ; Coronavirus RNA-Dependent RNA Polymerase (EC 2.7.7.48)
Language	English
Publishing date	2020-11-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Video-Audio Media
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-020-19843-1
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Article ; Online: Liquid-liquid phase separation of tau: From molecular biophysics to physiology and disease.

Rai, Sandeep K / Savastano, Adriana / Singh, Priyanka / Mukhopadhyay, Samrat / Zweckstetter, Markus

Protein science : a publication of the Protein Society

2021 Volume 30, Issue 7, Page(s) 1294–1314

Abstract: Biomolecular condensation via liquid-liquid phase separation (LLPS) of intrinsically disordered proteins/regions (IDPs/IDRs), with and without nucleic acids, has drawn widespread interest due to the rapidly unfolding role of phase-separated condensates ... ...

Abstract	Biomolecular condensation via liquid-liquid phase separation (LLPS) of intrinsically disordered proteins/regions (IDPs/IDRs), with and without nucleic acids, has drawn widespread interest due to the rapidly unfolding role of phase-separated condensates in a diverse range of cellular functions and human diseases. Biomolecular condensates form via transient and multivalent intermolecular forces that sequester proteins and nucleic acids into liquid-like membrane-less compartments. However, aberrant phase transitions into gel-like or solid-like aggregates might play an important role in neurodegenerative and other diseases. Tau, a microtubule-associated neuronal IDP, is involved in microtubule stabilization, regulates axonal outgrowth and transport in neurons. A growing body of evidence indicates that tau can accomplish some of its cellular activities via LLPS. However, liquid-to-solid transition resulting in the abnormal aggregation of tau is associated with neurodegenerative diseases. The physical chemistry of tau is crucial for governing its propensity for biomolecular condensation which is governed by various intermolecular and intramolecular interactions leading to simple one-component and complex multi-component condensates. In this review, we aim at capturing the current scientific state in unveiling the intriguing molecular mechanism of phase separation of tau. We particularly focus on the amalgamation of existing and emerging biophysical tools that offer unique spatiotemporal resolutions on a wide range of length- and time-scales. We also discuss the link between quantitative biophysical measurements and novel biological insights into biomolecular condensation of tau. We believe that this account will provide a broad and multidisciplinary view of phase separation of tau and its association with physiology and disease.
MeSH term(s)	Biomolecular Condensates/chemistry ; Humans ; Intrinsically Disordered Proteins/chemistry ; Intrinsically Disordered Proteins/isolation & purification ; Intrinsically Disordered Proteins/metabolism ; Neurodegenerative Diseases/metabolism ; tau Proteins/chemistry ; tau Proteins/isolation & purification ; tau Proteins/metabolism
Chemical Substances	Intrinsically Disordered Proteins ; MAPT protein, human ; tau Proteins
Language	English
Publishing date	2021-05-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1106283-6
ISSN	1469-896X ; 0961-8368
ISSN (online)	1469-896X
ISSN	0961-8368
DOI	10.1002/pro.4093
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Zs.A 3407: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: The pathogenic R5L mutation disrupts formation of Tau complexes on the microtubule by altering local N-terminal structure.

Cario, Alisa / Savastano, Adriana / Wood, Neil B / Liu, Zhu / Previs, Michael J / Hendricks, Adam G / Zweckstetter, Markus / Berger, Christopher L

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 7

Abstract: The microtubule-associated protein (MAP) Tau is an intrinsically disordered protein (IDP) primarily expressed in axons, where it functions to regulate microtubule dynamics, modulate motor protein motility, and participate in signaling cascades. Tau ... ...

Abstract	The microtubule-associated protein (MAP) Tau is an intrinsically disordered protein (IDP) primarily expressed in axons, where it functions to regulate microtubule dynamics, modulate motor protein motility, and participate in signaling cascades. Tau misregulation and point mutations are linked to neurodegenerative diseases, including progressive supranuclear palsy (PSP), Pick's disease, and Alzheimer's disease. Many disease-associated mutations in Tau occur in the C-terminal microtubule-binding domain of the protein. Effects of C-terminal mutations in Tau have led to the widely accepted disease-state theory that missense mutations in Tau reduce microtubule-binding affinity or increase Tau propensity to aggregate. Here, we investigate the effect of an N-terminal arginine to leucine mutation at position 5 in Tau (R5L), associated with PSP, on Tau-microtubule interactions using an in vitro reconstituted system. Contrary to the canonical disease-state theory, we determine that the R5L mutation does not reduce Tau affinity for the microtubule using total internal reflection fluorescence microscopy. Rather, the R5L mutation decreases the ability of Tau to form larger-order complexes, or Tau patches, at high concentrations of Tau. Using NMR, we show that the R5L mutation results in a local structural change that reduces interactions of the projection domain in the presence of microtubules. Altogether, these results challenge both the current paradigm of how mutations in Tau lead to disease and the role of the projection domain in modulating Tau behavior on the microtubule surface.
MeSH term(s)	Amino Acid Sequence ; Amino Acid Substitution ; Humans ; Microtubules/chemistry ; Microtubules/genetics ; Microtubules/metabolism ; Mutation ; tau Proteins/chemistry ; tau Proteins/genetics ; tau Proteins/metabolism
Chemical Substances	tau Proteins
Language	English
Publishing date	2022-02-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2114215119
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Article ; Online: Nucleocapsid protein of SARS-CoV-2 phase separates into RNA-rich polymerase-containing condensates

Adriana Savastano / Alain Ibáñez de Opakua / Marija Rankovic / Markus Zweckstetter

Nature Communications, Vol 11, Iss 1, Pp 1-

2020 Volume 10

Abstract: The SARS-CoV-2 viral genome is encapsulated by the nucleocapsid protein (NSARS-CoV-2) that is essential for viral replication. Here, the authors show that RNA induces liquid-liquid phase separation of NSARS-CoV-2 and how NSARS-CoV-2 phosphorylation ... ...

Abstract	The SARS-CoV-2 viral genome is encapsulated by the nucleocapsid protein (NSARS-CoV-2) that is essential for viral replication. Here, the authors show that RNA induces liquid-liquid phase separation of NSARS-CoV-2 and how NSARS-CoV-2 phosphorylation modulates RNA-binding and phase separation and that these RNA/NSARS-CoV-2-droplets recruit and concentrate the SARS-CoV-2 RNA-dependent RNA polymerase complex in vitro, which would enable high initiation and elongation rates during viral transcription.
Keywords	Science ; Q
Language	English
Publishing date	2020-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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