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Article ; Online: Liquid-liquid phase separation of the prion protein is regulated by the octarepeat domain independently of histidines and copper.

Kamps, Janine / Bader, Verian / Winklhofer, Konstanze F / Tatzelt, Jörg

2024 , Page(s) 107310

Abstract: Liquid-liquid phase separation (LLPS) of the mammalian prion protein is mainly driven by its intrinsically disordered N-terminal domain (N-PrP). However, the specific intermolecular interactions that promote LLPS remain largely unknown. Here, we used ... ...

Abstract	Liquid-liquid phase separation (LLPS) of the mammalian prion protein is mainly driven by its intrinsically disordered N-terminal domain (N-PrP). However, the specific intermolecular interactions that promote LLPS remain largely unknown. Here, we used extensive mutagenesis and comparative analyses of evolutionarily distant PrP species to gain insight into the relationship between protein sequence and phase behavior. LLPS of mouse PrP is dependent on two polybasic motifs in N-PrP that are conserved in all tetrapods. A unique feature of mammalian N-PrP is the octarepeat domain with four histidines that mediate binding to copper ions. We now show that the octarepeat is critical for promoting LLPS and preventing formation of PrP aggregates. Amphibian N-PrP, which contains the polybasic motifs but lacks a repeat domain and histidines, does not undergo LLPS and forms non-dynamic protein assemblies indicative of aggregates. Insertion of the mouse octarepeat domain restored LLPS of amphibian N-PrP, supporting its essential role in regulating phase transition of PrP. This activity of the octarepeat domain was neither dependent on the four highly conserved histidines nor on copper binding. Instead, the regularly spaced tryptophan residues were critical for regulating LLPS, presumably via cation-π interactions with the polybasic motifs. Our study reveals a novel role for the tryptophan residues in the octarepeat in controlling phase transition of PrP and indicates that the ability of mammalian PrP to undergo LLPS has evolved with the octarepeat in the intrinsically disordered domain, but independently of the histidines.
Language	English
Publishing date	2024-04-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2024.107310
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Article: The Role of Ubiquitin in Regulating Stress Granule Dynamics.

Krause, Laura J / Herrera, Maria G / Winklhofer, Konstanze F

Frontiers in physiology

2022 Volume 13, Page(s) 910759

Abstract: Stress granules (SGs) are dynamic, reversible biomolecular condensates, which assemble in the cytoplasm of eukaryotic cells under various stress conditions. Formation of SGs typically occurs upon stress-induced translational arrest and polysome ... ...

Abstract	Stress granules (SGs) are dynamic, reversible biomolecular condensates, which assemble in the cytoplasm of eukaryotic cells under various stress conditions. Formation of SGs typically occurs upon stress-induced translational arrest and polysome disassembly. The increase in cytoplasmic mRNAs triggers the formation of a protein-RNA network that undergoes liquid-liquid phase separation when a critical interaction threshold has been reached. This adaptive stress response allows a transient shutdown of several cellular processes until the stress is removed. During the recovery from stress, SGs disassemble to re-establish cellular activities. Persistent stress and disease-related mutations in SG components favor the formation of aberrant SGs that are impaired in disassembly and prone to aggregation. Recently, posttranslational modifications of SG components have been identified as major regulators of SG dynamics. Here, we summarize new insights into the role of ubiquitination in affecting SG dynamics and clearance and discuss implications for neurodegenerative diseases linked to aberrant SG formation.
Language	English
Publishing date	2022-05-25
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2022.910759
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Article: Linear Ubiquitin Chains: Cellular Functions and Strategies for Detection and Quantification.

Dittmar, Gunnar / Winklhofer, Konstanze F

Frontiers in chemistry

2020 Volume 7, Page(s) 915

Abstract: Ubiquitination of proteins is a sophisticated post-translational modification implicated in the regulation of an ever-growing abundance of cellular processes. Recent insights into different layers of complexity have shaped the concept of the ubiquitin ... ...

Abstract	Ubiquitination of proteins is a sophisticated post-translational modification implicated in the regulation of an ever-growing abundance of cellular processes. Recent insights into different layers of complexity have shaped the concept of the ubiquitin code. Key players in determining this code are the number of ubiquitin moieties attached to a substrate, the architecture of polyubiquitin chains, and post-translational modifications of ubiquitin itself. Ubiquitination can induce conformational changes of substrates and alter their interactive profile, resulting in the formation of signaling complexes. Here we focus on a distinct type of ubiquitination that is characterized by an inter-ubiquitin linkage through the N-terminal methionine, called M1-linked or linear ubiquitination. Formation, recognition, and disassembly of linear ubiquitin chains are highly specific processes that are implicated in immune signaling, cell death regulation and protein quality control. Consistent with their role in influencing signaling events, linear ubiquitin chains are formed in a transient and spatially regulated manner, making their detection and quantification challenging.
Language	English
Publishing date	2020-01-10
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2711776-5
ISSN	2296-2646
ISSN	2296-2646
DOI	10.3389/fchem.2019.00915
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Article ; Online: PINK1 and Parkin: team players in stress-induced mitophagy.

Bader, Verian / Winklhofer, Konstanze F

Biological chemistry

2020 Volume 401, Issue 6-7, Page(s) 891–899

Abstract: Mitochondria are highly vulnerable organelles based on their complex biogenesis, entailing dependence on nuclear gene expression and efficient import strategies. They are implicated in a wide spectrum of vital cellular functions, including oxidative ... ...

Abstract	Mitochondria are highly vulnerable organelles based on their complex biogenesis, entailing dependence on nuclear gene expression and efficient import strategies. They are implicated in a wide spectrum of vital cellular functions, including oxidative phosphorylation, iron-sulfur cluster synthesis, regulation of calcium homeostasis, and apoptosis. Moreover, damaged mitochondria can release mitochondrial components, such as mtDNA or cardiolipin, which are sensed as danger-associated molecular patterns and trigger innate immune signaling. Thus, dysfunctional mitochondria pose a thread not only to the cellular but also to the organismal integrity. The elimination of dysfunctional and damaged mitochondria by selective autophagy, called mitophagy, is a major mechanism of mitochondrial quality control. Certain types of stress-induced mitophagy are regulated by the mitochondrial kinase PINK1 and the E3 ubiquitin ligase Parkin, which are both linked to autosomal recessive Parkinson's disease.
MeSH term(s)	Humans ; Mitochondria/genetics ; Mitochondria/metabolism ; Mitophagy ; Neurons/metabolism ; Oxidative Stress ; Parkinson Disease/genetics ; Parkinson Disease/metabolism ; Protein Kinases/genetics ; Protein Kinases/metabolism ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	Ubiquitin-Protein Ligases (EC 2.3.2.27) ; parkin protein (EC 2.3.2.27) ; Protein Kinases (EC 2.7.-) ; PTEN-induced putative kinase (EC 2.7.11.1)
Language	English
Publishing date	2020-04-16
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1334659-3
ISSN	1437-4315 ; 1431-6730 ; 1432-0355
ISSN (online)	1437-4315
ISSN	1431-6730 ; 1432-0355
DOI	10.1515/hsz-2020-0135
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Article ; Online: Mitochondria at the interface between neurodegeneration and neuroinflammation.

Bader, Verian / Winklhofer, Konstanze F

Seminars in cell & developmental biology

2019 Volume 99, Page(s) 163–171

Abstract: Mitochondria are essential organelles for the maintenance of neuronal integrity, based on their manifold functions in regulating cellular metabolism and coordinating cell death and viability pathways. Accordingly, mitochondrial damage, dysfunction, or ... ...

Abstract	Mitochondria are essential organelles for the maintenance of neuronal integrity, based on their manifold functions in regulating cellular metabolism and coordinating cell death and viability pathways. Accordingly, mitochondrial damage, dysfunction, or ineffective mitochondrial quality control is associated with neurological disorders and can occur as a cause or consequence of neurodegenerative diseases. Recent research revealed that mitochondria play a central role in orchestrating both innate and adaptive immune responses, thereby providing a link between neurodegenerative and neuroinflammatory processes. Here we summarize new insights into the complex interplay between mitochondria, innate immunity and neurodegeneration.
MeSH term(s)	Animals ; Humans ; Inflammation/metabolism ; Inflammation/pathology ; Mitochondria/metabolism ; Mitochondria/pathology ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/pathology ; Neurons/metabolism ; Neurons/pathology
Language	English
Publishing date	2019-06-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1312473-0
ISSN	1096-3634 ; 1084-9521
ISSN (online)	1096-3634
ISSN	1084-9521
DOI	10.1016/j.semcdb.2019.05.028
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Article ; Online: VCP/p97 mediates nuclear targeting of non-ER-imported prion protein to maintain proteostasis.

Banik, Papiya / Ray, Koustav / Kamps, Janine / Chen, Qi-Yin / Luesch, Hendrik / Winklhofer, Konstanze F / Tatzelt, Jörg

Life science alliance

2024 Volume 7, Issue 6

Abstract: Mistargeting of secretory proteins in the cytosol can trigger their aggregation and subsequent proteostasis decline. We have identified a VCP/p97-dependent pathway that directs non-ER-imported prion protein (PrP) into the nucleus to prevent the formation ...

Abstract	Mistargeting of secretory proteins in the cytosol can trigger their aggregation and subsequent proteostasis decline. We have identified a VCP/p97-dependent pathway that directs non-ER-imported prion protein (PrP) into the nucleus to prevent the formation of toxic aggregates in the cytosol. Upon impaired translocation into the ER, PrP interacts with VCP/p97, which facilitates nuclear import mediated by importin-ß. Notably, the cytosolic interaction of PrP with VCP/p97 and its nuclear import are independent of ubiquitination. In vitro experiments revealed that VCP/p97 binds non-ubiquitinated PrP and prevents its aggregation. Inhibiting binding of PrP to VCP/p97, or transient proteotoxic stress, promotes the formation of self-perpetuating and partially proteinase resistant PrP aggregates in the cytosol, which compromised cellular proteostasis and disrupted further nuclear targeting of PrP. In the nucleus, RNAs keep PrP in a soluble and non-toxic conformation. Our study revealed a novel ubiquitin-independent role of VCP/p97 in the nuclear targeting of non-imported secretory proteins and highlights the impact of the chemical milieu in triggering protein misfolding.
MeSH term(s)	Prion Proteins/metabolism ; Valosin Containing Protein/metabolism ; Adenosine Triphosphatases/metabolism ; Proteostasis ; Ubiquitin/metabolism ; Prions/metabolism
Chemical Substances	Prion Proteins ; Valosin Containing Protein (EC 3.6.4.6) ; Adenosine Triphosphatases (EC 3.6.1.-) ; Ubiquitin ; Prions
Language	English
Publishing date	2024-04-03
Publishing country	United States
Document type	Journal Article
ISSN	2575-1077
ISSN (online)	2575-1077
DOI	10.26508/lsa.202302456
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Article ; Online: Hydration makes a difference! How to tune protein complexes between liquid-liquid and liquid-solid phase separation.

Ramos, Sashary / Kamps, Janine / Pezzotti, Simone / Winklhofer, Konstanze F / Tatzelt, Jörg / Havenith, Martina

Physical chemistry chemical physics : PCCP

2023 Volume 25, Issue 41, Page(s) 28063–28069

Abstract: Understanding how protein rich condensates formed upon liquid-liquid phase separation (LLPS) evolve into solid aggregates is of fundamental importance for several medical applications, since these are suspected to be hot-spots for many neurotoxic ... ...

Abstract	Understanding how protein rich condensates formed upon liquid-liquid phase separation (LLPS) evolve into solid aggregates is of fundamental importance for several medical applications, since these are suspected to be hot-spots for many neurotoxic diseases. This requires developing experimental approaches to observe in real-time both LLPS and liquid-solid phase separation (LSPS), and to unravel the delicate balance of protein and water interactions dictating the free energy differences between the two. We present a vibrational THz spectroscopy approach that allows doing so from the point of view of hydration water. We focus on a cellular prion protein of high medical relevance, which we can drive to undergo either LLPS or LSPS with few mutations. We find that it is a subtle balance of hydrophobic and hydrophilic solvation contributions that allows tuning between LLPS and LSPS. Hydrophobic hydration provides an entropic driving force to phase separation, through the release of hydration water into the bulk. Water hydrating hydrophilic groups provides an enthalpic driving force to keep the condensates in a liquid state. As a result, when we modify the protein by a few mutations to be less hydrophilic, we shift from LLPS to LSPS. This molecular understanding paves the way for a rational design of proteins.
MeSH term(s)	Proteins/chemistry ; Thermodynamics ; Entropy ; Hydrophobic and Hydrophilic Interactions ; Water/chemistry
Chemical Substances	Proteins ; Water (059QF0KO0R)
Language	English
Publishing date	2023-10-25
Publishing country	England
Document type	Journal Article
ZDB-ID	1476244-4
ISSN	1463-9084 ; 1463-9076
ISSN (online)	1463-9084
ISSN	1463-9076
DOI	10.1039/d3cp03299j
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Article ; Online: Parkin and mitochondrial quality control: toward assembling the puzzle.

Winklhofer, Konstanze F

Trends in cell biology

2014 Volume 24, Issue 6, Page(s) 332–341

Abstract: Parkin is an E3 ubiquitin ligase associated with autosomal-recessive Parkinsonism. Moreover, parkin inactivation has been found in sporadic Parkinson's disease (PD), suggesting a wider pathogenic impact than initially predicted. Beyond its role in PD, ... ...

Abstract	Parkin is an E3 ubiquitin ligase associated with autosomal-recessive Parkinsonism. Moreover, parkin inactivation has been found in sporadic Parkinson's disease (PD), suggesting a wider pathogenic impact than initially predicted. Beyond its role in PD, parkin has also been implicated in innate immune responses. Since its discovery, mounting evidence indicates that parkin can mediate degradative as well as nondegradative ubiquitination. Here we review recent insights into the structure of parkin, the mechanism of its E3 ligase activity, and its functional versatility in an attempt to merge controversial aspects into a more comprehensive picture of this multifaceted E3 ubiquitin ligase.
MeSH term(s)	Animals ; Humans ; Immunity, Innate ; Mitochondria/physiology ; Proteasome Endopeptidase Complex/metabolism ; Ubiquitin-Protein Ligases/chemistry ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	Ubiquitin-Protein Ligases (EC 2.3.2.27) ; parkin protein (EC 2.3.2.27) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2014-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	30122-x
ISSN	1879-3088 ; 0962-8924
ISSN (online)	1879-3088
ISSN	0962-8924
DOI	10.1016/j.tcb.2014.01.001
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Article ; Online: Protein quality control by the proteasome and autophagy: A regulatory role of ubiquitin and liquid-liquid phase separation.

Lei, Linlin / Wu, Zhixiao / Winklhofer, Konstanze F

Matrix biology : journal of the International Society for Matrix Biology

2020 Volume 100-101, Page(s) 9–22

Abstract: Degradation of dysfunctional, damaged, or misfolded proteins is a crucial component of the protein quality control network to maintain cellular proteostasis. Dysfunction in proteostasis regulation due to imbalances in protein synthesis, folding, and ... ...

Abstract	Degradation of dysfunctional, damaged, or misfolded proteins is a crucial component of the protein quality control network to maintain cellular proteostasis. Dysfunction in proteostasis regulation due to imbalances in protein synthesis, folding, and degradation challenges the integrity of the cellular proteome and favors the accumulation of aggregated proteins that can damage cells by a loss of their functions and/or a gain of adverse functions. Ubiquitination is an essential player in proteostasis regulation but also in orchestrating signaling pathways in response to various stress conditions. Both cellular degradation systems, the proteasome and autophagy, employ ubiquitin for selection and targeting of substrates to the degradative machineries. Here we summarize the manifold functions of ubiquitin in protein degradation and discuss its emerging role in the formation of biomolecular condensates through liquid-liquid phase separation, which allows spatiotemporal regulation of protein quality control.
MeSH term(s)	Autophagy ; Biomolecular Condensates ; Proteasome Endopeptidase Complex/metabolism ; Ubiquitin/metabolism ; Ubiquitination
Chemical Substances	Ubiquitin ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2020-11-28
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1183793-7
ISSN	1569-1802 ; 0945-053X
ISSN (online)	1569-1802
ISSN	0945-053X
DOI	10.1016/j.matbio.2020.11.003
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Article: Brevican, Neurocan, Tenascin-C, and Tenascin-R Act as Important Regulators of the Interplay Between Perineuronal Nets, Synaptic Integrity, Inhibitory Interneurons, and Otx2.

Mueller-Buehl, Cornelius / Reinhard, Jacqueline / Roll, Lars / Bader, Verian / Winklhofer, Konstanze F / Faissner, Andreas

Frontiers in cell and developmental biology

2022 Volume 10, Page(s) 886527

Abstract: Fast-spiking parvalbumin interneurons are critical for the function of mature cortical inhibitory circuits. Most of these neurons are enwrapped by a specialized extracellular matrix (ECM) structure called perineuronal net (PNN), which can regulate their ... ...

Abstract	Fast-spiking parvalbumin interneurons are critical for the function of mature cortical inhibitory circuits. Most of these neurons are enwrapped by a specialized extracellular matrix (ECM) structure called perineuronal net (PNN), which can regulate their synaptic input. In this study, we investigated the relationship between PNNs, parvalbumin interneurons, and synaptic distribution on these cells in the adult primary visual cortex (V1) of quadruple knockout mice deficient for the ECM molecules brevican, neurocan, tenascin-C, and tenascin-R. We used super-resolution structured illumination microscopy (SIM) to analyze PNN structure and associated synapses. In addition, we examined parvalbumin and calretinin interneuron populations. We observed a reduction in the number of PNN-enwrapped cells and clear disorganization of the PNN structure in the quadruple knockout V1. This was accompanied by an imbalance of inhibitory and excitatory synapses with a reduction of inhibitory and an increase of excitatory synaptic elements along the PNNs. Furthermore, the number of parvalbumin interneurons was reduced in the quadruple knockout, while calretinin interneurons, which do not wear PNNs, did not display differences in number. Interestingly, we found the transcription factor Otx2 homeoprotein positive cell population also reduced. Otx2 is crucial for parvalbumin interneuron and PNN maturation, and a positive feedback loop between these parameters has been described. Collectively, these data indicate an important role of brevican, neurocan, tenascin-C, and tenascin-R in regulating the interplay between PNNs, inhibitory interneurons, synaptic distribution, and Otx2 in the V1.
Language	English
Publishing date	2022-06-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2022.886527
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