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Article ; Online: Voltage-activated complexation of α-synuclein with three diverse β-barrel channels: VDAC, MspA, and α-hemolysin.

Hoogerheide, David P / Gurnev, Philip A / Rostovtseva, Tatiana K / Bezrukov, Sergey M

2021 Volume 22, Issue 5-6, Page(s) e2100060

Abstract: Voltage-activated complexation is the process by which a transmembrane potential drives complex formation between a membrane-embedded channel and a soluble or membrane-peripheral target protein. Metabolite and calcium flux across the mitochondrial outer ... ...

Abstract	Voltage-activated complexation is the process by which a transmembrane potential drives complex formation between a membrane-embedded channel and a soluble or membrane-peripheral target protein. Metabolite and calcium flux across the mitochondrial outer membrane was shown to be regulated by voltage-activated complexation of the voltage-dependent anion channel (VDAC) and either dimeric tubulin or α-synuclein (αSyn). However, the roles played by VDAC's characteristic attributes-its anion selectivity and voltage gating behavior-have remained unclear. Here, we compare in vitro measurements of voltage-activated complexation of αSyn with three well-characterized β-barrel channels-VDAC, MspA, and α-hemolysin-that differ widely in their organism of origin, structure, geometry, charge density distribution, and voltage gating behavior. The voltage dependences of the complexation dynamics for the different channels are observed to differ quantitatively but have similar qualitative features. In each case, energy landscape modeling describes the complexation dynamics in a manner consistent with the known properties of the individual channels, while voltage gating does not appear to play a role. The reaction free energy landscapes thus calculated reveal a non-trivial dependence of the αSyn/channel complex stability on the surface density of αSyn.
MeSH term(s)	Anions/metabolism ; Hemolysin Proteins/metabolism ; Mitochondrial Membranes/metabolism ; Voltage-Dependent Anion Channels/chemistry ; Voltage-Dependent Anion Channels/metabolism ; alpha-Synuclein/metabolism
Chemical Substances	Anions ; Hemolysin Proteins ; Voltage-Dependent Anion Channels ; alpha-Synuclein
Language	English
Publishing date	2021-12-06
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2032093-0
ISSN	1615-9861 ; 1615-9853
ISSN (online)	1615-9861
ISSN	1615-9853
DOI	10.1002/pmic.202100060
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Zs.A 5386: 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)
Zs.A 1868: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Effect of a post-translational modification mimic on protein translocation through a nanopore.

Hoogerheide, David P / Gurnev, Philip A / Rostovtseva, Tatiana K / Bezrukov, Sergey M

Nanoscale

2020 Volume 12, Issue 20, Page(s) 11070–11078

Abstract: Post-translational modifications (PTMs) of proteins are recognized as crucial components of cell signaling pathways through modulating folding, altering stability, changing interactions with ligands, and, therefore, serving multiple regulatory functions. ...

Abstract	Post-translational modifications (PTMs) of proteins are recognized as crucial components of cell signaling pathways through modulating folding, altering stability, changing interactions with ligands, and, therefore, serving multiple regulatory functions. PTMs occur as covalent modifications of the protein's amino acid side chains or the length and composition of their termini. Here we study the functional consequences of PTMs for α-synuclein (αSyn) interactions with the nanopore of the voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane. PTMs were mimicked by a divalent Alexa Fluor 488 sidechain attached separately at two positions on the αSyn C-terminus. Using single-channel reconstitution into planar lipid membranes, we find that such modifications change interactions drastically in both efficiency of VDAC inhibition by αSyn and its translocation through the VDAC nanopore. Analysis of the on/off kinetics in terms of an interaction "quasipotential" allows the positions of the C-terminal modifications to be determined with an accuracy of about three residues. Moreover, our results uncover a previously unobserved mechanism by which cytosolic proteins control β-barrel channels and thus a new regulatory function for PTMs.
MeSH term(s)	Animals ; Mitochondria, Liver/chemistry ; Mitochondria, Liver/metabolism ; Mitochondrial Membranes/chemistry ; Mitochondrial Membranes/metabolism ; Nanopores ; Protein Processing, Post-Translational ; Protein Transport ; Rats ; alpha-Synuclein/chemistry ; alpha-Synuclein/metabolism
Chemical Substances	Snca protein, rat ; alpha-Synuclein
Language	English
Publishing date	2020-05-13
Publishing country	England
Document type	Journal Article
ZDB-ID	2515664-0
ISSN	2040-3372 ; 2040-3364
ISSN (online)	2040-3372
ISSN	2040-3364
DOI	10.1039/d0nr01577f
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Article ; Online: Tunable Electromechanical Nanopore Trap Reveals Populations of Peripheral Membrane Protein Binding Conformations.

Hoogerheide, David P / Rostovtseva, Tatiana K / Jacobs, Daniel / Gurnev, Philip A / Bezrukov, Sergey M

ACS nano

2020 Volume 15, Issue 1, Page(s) 989–1001

Abstract: We demonstrate that a naturally occurring nanopore, the voltage-dependent anion channel (VDAC) of the mitochondrion, can be used to electromechanically trap and interrogate proteins bound to a lipid surface at the single-molecule level. ... ...

Abstract	We demonstrate that a naturally occurring nanopore, the voltage-dependent anion channel (VDAC) of the mitochondrion, can be used to electromechanically trap and interrogate proteins bound to a lipid surface at the single-molecule level. Electromechanically probing α-synuclein (αSyn), an intrinsically disordered neuronal protein intimately associated with Parkinson's pathology, reveals wide variation in the time required for individual proteins to unbind from the same membrane surface. The observed distributions of unbinding times span up to 3 orders of magnitude and depend strongly on the lipid composition of the membrane; surprisingly, lipid membranes to which αSyn binds weakly are most likely to contain subpopulations in which electromechanically driven unbinding is very slow. We conclude that unbinding of αSyn from the membrane surface depends not only on membrane binding affinity but also on the conformation adopted by an individual αSyn molecule on the membrane surface.
MeSH term(s)	Membrane Proteins/metabolism ; Mitochondria/metabolism ; Molecular Conformation ; Nanopores ; Protein Binding ; alpha-Synuclein/metabolism
Chemical Substances	Membrane Proteins ; alpha-Synuclein
Language	English
Publishing date	2020-12-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	1936-086X
ISSN (online)	1936-086X
DOI	10.1021/acsnano.0c07672
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Article ; Online: Channel-forming bacterial toxins in biosensing and macromolecule delivery.

Gurnev, Philip A / Nestorovich, Ekaterina M

Toxins

2014 Volume 6, Issue 8, Page(s) 2483–2540

Abstract: To intoxicate cells, pore-forming bacterial toxins are evolved to allow for the transmembrane traffic of different substrates, ranging from small inorganic ions to cell-specific polypeptides. Recent developments in single-channel electrical recordings, X- ...

Abstract	To intoxicate cells, pore-forming bacterial toxins are evolved to allow for the transmembrane traffic of different substrates, ranging from small inorganic ions to cell-specific polypeptides. Recent developments in single-channel electrical recordings, X-ray crystallography, protein engineering, and computational methods have generated a large body of knowledge about the basic principles of channel-mediated molecular transport. These discoveries provide a robust framework for expansion of the described principles and methods toward use of biological nanopores in the growing field of nanobiotechnology. This article, written for a special volume on "Intracellular Traffic and Transport of Bacterial Protein Toxins", reviews the current state of applications of pore-forming bacterial toxins in small- and macromolecule-sensing, targeted cancer therapy, and drug delivery. We discuss the electrophysiological studies that explore molecular details of channel-facilitated protein and polymer transport across cellular membranes using both natural and foreign substrates. The review focuses on the structurally and functionally different bacterial toxins: gramicidin A of Bacillus brevis, α-hemolysin of Staphylococcus aureus, and binary toxin of Bacillus anthracis, which have found their "second life" in a variety of developing medical and technological applications.
MeSH term(s)	Animals ; Bacterial Proteins/metabolism ; Bacterial Proteins/therapeutic use ; Bacterial Toxins/metabolism ; Bacterial Toxins/therapeutic use ; Biological Transport ; Biosensing Techniques ; Drug Delivery Systems ; Humans ; Neoplasms/drug therapy ; Pore Forming Cytotoxic Proteins/metabolism ; Pore Forming Cytotoxic Proteins/therapeutic use
Chemical Substances	Bacterial Proteins ; Bacterial Toxins ; Pore Forming Cytotoxic Proteins
Language	English
Publishing date	2014-08-21
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	2518395-3
ISSN	2072-6651 ; 2072-6651
ISSN (online)	2072-6651
ISSN	2072-6651
DOI	10.3390/toxins6082483
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Article ; Online: Real-Time Nanopore-Based Recognition of Protein Translocation Success.

Hoogerheide, David P / Gurnev, Philip A / Rostovtseva, Tatiana K / Bezrukov, Sergey M

Biophysical journal

2018 Volume 114, Issue 4, Page(s) 772–776

Abstract: A growing number of new technologies are supported by a single- or multi-nanopore architecture for capture, sensing, and delivery of polymeric biomolecules. Nanopore-based single-molecule DNA sequencing is the premier example. This method relies on the ... ...

Abstract	A growing number of new technologies are supported by a single- or multi-nanopore architecture for capture, sensing, and delivery of polymeric biomolecules. Nanopore-based single-molecule DNA sequencing is the premier example. This method relies on the uniform linear charge density of DNA, so that each DNA strand is overwhelmingly likely to pass through the nanopore and across the separating membrane. For disordered peptides, folded proteins, or block copolymers with heterogeneous charge densities, by contrast, translocation is not assured, and additional strategies to monitor the progress of the polymer molecule through a nanopore are required. Here, we demonstrate a single-molecule method for direct, model-free, real-time monitoring of the translocation of a disordered, heterogeneously charged polypeptide through a nanopore. The crucial elements are two "selectivity tags"-regions of different but uniform charge density-at the ends of the polypeptide. These affect the selectivity of the nanopore differently and enable discrimination between polypeptide translocation and retraction. Our results demonstrate exquisite sensitivity of polypeptide translocation to applied transmembrane potential and prove the principle that nanopore selectivity reports on biopolymer substructure. We anticipate that the selectivity tag technique will be broadly applicable to nanopore-based protein detection, analysis, and separation technologies, and to the elucidation of protein translocation processes in normal cellular function and in disease.
MeSH term(s)	Computer Simulation ; Humans ; Models, Molecular ; Nanopores ; Porosity ; Protein Transport ; Voltage-Dependent Anion Channels/chemistry ; Voltage-Dependent Anion Channels/metabolism
Chemical Substances	Voltage-Dependent Anion Channels
Language	English
Publishing date	2018-01-12
Publishing country	United States
Document type	Letter ; Research Support, N.I.H., Intramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2017.12.019
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Article ; Online: Correction to: Molecular mechanism of olesoxime-mediated neuroprotection through targeting α-synuclein interaction with mitochondrial VDAC.

Rovini, Amandine / Gurnev, Philip A / Beilina, Alexandra / Queralt-Martín, María / Rosencrans, William / Cookson, Mark R / Bezrukov, Sergey M / Rostovtseva, Tatiana K

Cellular and molecular life sciences : CMLS

2020 Volume 77, Issue 18, Page(s) 3691–3692

Abstract: In the published article, an error was noticed and this has been corrected with this erratum publication. ...

Abstract	In the published article, an error was noticed and this has been corrected with this erratum publication.
Language	English
Publishing date	2020-01-09
Publishing country	Switzerland
Document type	Journal Article ; Published Erratum
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-019-03417-6
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Article ; Online: Restricting α-synuclein transport into mitochondria by inhibition of α-synuclein-VDAC complexation as a potential therapeutic target for Parkinson's disease treatment.

Rajendran, Megha / Queralt-Martín, María / Gurnev, Philip A / Rosencrans, William M / Rovini, Amandine / Jacobs, Daniel / Abrantes, Kaitlin / Hoogerheide, David P / Bezrukov, Sergey M / Rostovtseva, Tatiana K

Cellular and molecular life sciences : CMLS

2022 Volume 79, Issue 7, Page(s) 368

Abstract: Involvement of alpha-synuclein (αSyn) in Parkinson's disease (PD) is complicated and difficult to trace on cellular and molecular levels. Recently, we established that αSyn can regulate mitochondrial function by voltage-activated complexation with the ... ...

Abstract	Involvement of alpha-synuclein (αSyn) in Parkinson's disease (PD) is complicated and difficult to trace on cellular and molecular levels. Recently, we established that αSyn can regulate mitochondrial function by voltage-activated complexation with the voltage-dependent anion channel (VDAC) on the mitochondrial outer membrane. When complexed with αSyn, the VDAC pore is partially blocked, reducing the transport of ATP/ADP and other metabolites. Further, αSyn can translocate into the mitochondria through VDAC, where it interferes with mitochondrial respiration. Recruitment of αSyn to the VDAC-containing lipid membrane appears to be a crucial prerequisite for both the blockage and translocation processes. Here we report an inhibitory effect of HK2p, a small membrane-binding peptide from the mitochondria-targeting N-terminus of hexokinase 2, on αSyn membrane binding, and hence on αSyn complex formation with VDAC and translocation through it. In electrophysiology experiments, the addition of HK2p at micromolar concentrations to the same side of the membrane as αSyn results in a dramatic reduction of the frequency of blockage events in a concentration-dependent manner, reporting on complexation inhibition. Using two complementary methods of measuring protein-membrane binding, bilayer overtone analysis and fluorescence correlation spectroscopy, we found that HK2p induces detachment of αSyn from lipid membranes. Experiments with HeLa cells using proximity ligation assay confirmed that HK2p impedes αSyn entry into mitochondria. Our results demonstrate that it is possible to regulate αSyn-VDAC complexation by a rationally designed peptide, thus suggesting new avenues in the search for peptide therapeutics to alleviate αSyn mitochondrial toxicity in PD and other synucleinopathies.
MeSH term(s)	HeLa Cells ; Humans ; Lipids ; Mitochondria/metabolism ; Parkinson Disease/drug therapy ; Parkinson Disease/metabolism ; Voltage-Dependent Anion Channels/metabolism ; alpha-Synuclein/metabolism
Chemical Substances	Lipids ; Voltage-Dependent Anion Channels ; alpha-Synuclein
Language	English
Publishing date	2022-06-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-022-04389-w
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Article ; Online: Inversion of membrane surface charge by trivalent cations probed with a cation-selective channel.

Gurnev, Philip A / Bezrukov, Sergey M

Langmuir : the ACS journal of surfaces and colloids

2012 Volume 28, Issue 45, Page(s) 15824–15830

Abstract: We demonstrate that the cation-selective channel formed by gramicidin A can be used as a reliable sensor for studying the multivalent ion accumulation at the surfaces of charged lipid membranes and the "charge inversion" phenomenon. In asymmetrically ... ...

Abstract	We demonstrate that the cation-selective channel formed by gramicidin A can be used as a reliable sensor for studying the multivalent ion accumulation at the surfaces of charged lipid membranes and the "charge inversion" phenomenon. In asymmetrically charged membranes with the individual leaflets formed from pure negative and positive lipids bathed by 0.1 M CsCl solutions the channel exhibits current rectification, which is comparable to that of a typical n/p semiconductor diode. We show that even at these highly asymmetrical conditions the channel conductance can be satisfactorily described by the electrodiffusion equation in the constant field approximation but, due to predictable limitations, only when the applied voltages do not exceed 50 mV. Analysis of the changes in the voltage-dependent channel conductance upon addition of trivalent cations allows us to gauge their interactions with the membrane surface. The inversion of the sign of the effective surface charge takes place at the concentrations, which correlate with the cation size. Specifically, these concentrations are close to 0.05 mM for lanthanum, 0.25 mM for hexaamminecobalt, and 4 mM for spermidine.
MeSH term(s)	Cations/chemistry ; Cesium/chemistry ; Chlorides/chemistry ; Electric Conductivity ; Gramicidin/chemistry ; Lipid Bilayers/chemistry ; Semiconductors ; Solutions ; Surface Properties
Chemical Substances	Cations ; Chlorides ; Lipid Bilayers ; Solutions ; Gramicidin (1405-97-6) ; Cesium (1KSV9V4Y4I) ; cesium chloride (GNR9HML8BA)
Language	English
Publishing date	2012-11-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2005937-1
ISSN	1520-5827 ; 0743-7463
ISSN (online)	1520-5827
ISSN	0743-7463
DOI	10.1021/la302676t
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Article ; Online: The antiarrhythmic compound efsevin directly modulates voltage-dependent anion channel 2 by binding to its inner wall and enhancing mitochondrial Ca

Wilting, Fabiola / Kopp, Robin / Gurnev, Philip A / Schedel, Anna / Dupper, Nathan J / Kwon, Ohyun / Nicke, Annette / Gudermann, Thomas / Schredelseker, Johann

British journal of pharmacology

2020 Volume 177, Issue 13, Page(s) 2947–2958

Abstract: Background and purpose: The synthetic compound efsevin was recently identified to suppress arrhythmogenesis in models of cardiac arrhythmia, making it a promising candidate for antiarrhythmic therapy. Its activity was shown to be dependent on the ... ...

Abstract	Background and purpose: The synthetic compound efsevin was recently identified to suppress arrhythmogenesis in models of cardiac arrhythmia, making it a promising candidate for antiarrhythmic therapy. Its activity was shown to be dependent on the voltage-dependent anion channel 2 (VDAC2) in the outer mitochondrial membrane. Here, we investigated the molecular mechanism of the efsevin-VDAC2 interaction. Experimental approach: To evaluate the functional interaction of efsevin and VDAC2, we measured currents through recombinant VDAC2 in planar lipid bilayers. Using molecular ligand-protein docking and mutational analysis, we identified the efsevin binding site on VDAC2. Finally, physiological consequences of the efsevin-induced modulation of VDAC2 were analysed in HL-1 cardiomyocytes. Key results: In lipid bilayers, efsevin reduced VDAC2 conductance and shifted the channel's open probability towards less anion-selective closed states. Efsevin binds to a binding pocket formed by the inner channel wall and the pore-lining N-terminal α-helix. Exchange of amino acids N207, K236 and N238 within this pocket for alanines abolished the channel's efsevin-responsiveness. Upon heterologous expression in HL-1 cardiomyocytes, both channels, wild-type VDAC2 and the efsevin-insensitive VDAC2 Conclusion and implications: In summary, our data indicate a direct interaction of efsevin with VDAC2 inside the channel pore that leads to modified gating and results in enhanced SR-mitochondria Ca
MeSH term(s)	Animals ; Biological Transport ; Calcium/metabolism ; Mitochondria/metabolism ; Mitochondrial Membranes/metabolism ; Myocytes, Cardiac/metabolism ; Voltage-Dependent Anion Channel 2/agonists ; Voltage-Dependent Anion Channel 2/metabolism ; Zebrafish ; Zebrafish Proteins
Chemical Substances	Voltage-Dependent Anion Channel 2 ; Zebrafish Proteins ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2020-03-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/bph.15022
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Article: Restricting α-synuclein transport into mitochondria by inhibition of α-synuclein–VDAC complexation as a potential therapeutic target for Parkinson’s disease treatment

Rajendran, Megha / Queralt-Martín, María / Gurnev, Philip A. / Rosencrans, William M. / Rovini, Amandine / Jacobs, Daniel / Abrantes, Kaitlin / Hoogerheide, David P. / Bezrukov, Sergey M. / Rostovtseva, Tatiana K.

Cellular and molecular life sciences. 2022 July, v. 79, no. 7

2022

Abstract: Involvement of alpha-synuclein (αSyn) in Parkinson’s disease (PD) is complicated and difficult to trace on cellular and molecular levels. Recently, we established that αSyn can regulate mitochondrial function by voltage-activated complexation with the ... ...

Abstract	Involvement of alpha-synuclein (αSyn) in Parkinson’s disease (PD) is complicated and difficult to trace on cellular and molecular levels. Recently, we established that αSyn can regulate mitochondrial function by voltage-activated complexation with the voltage-dependent anion channel (VDAC) on the mitochondrial outer membrane. When complexed with αSyn, the VDAC pore is partially blocked, reducing the transport of ATP/ADP and other metabolites. Further, αSyn can translocate into the mitochondria through VDAC, where it interferes with mitochondrial respiration. Recruitment of αSyn to the VDAC-containing lipid membrane appears to be a crucial prerequisite for both the blockage and translocation processes. Here we report an inhibitory effect of HK2p, a small membrane-binding peptide from the mitochondria-targeting N-terminus of hexokinase 2, on αSyn membrane binding, and hence on αSyn complex formation with VDAC and translocation through it. In electrophysiology experiments, the addition of HK2p at micromolar concentrations to the same side of the membrane as αSyn results in a dramatic reduction of the frequency of blockage events in a concentration-dependent manner, reporting on complexation inhibition. Using two complementary methods of measuring protein-membrane binding, bilayer overtone analysis and fluorescence correlation spectroscopy, we found that HK2p induces detachment of αSyn from lipid membranes. Experiments with HeLa cells using proximity ligation assay confirmed that HK2p impedes αSyn entry into mitochondria. Our results demonstrate that it is possible to regulate αSyn–VDAC complexation by a rationally designed peptide, thus suggesting new avenues in the search for peptide therapeutics to alleviate αSyn mitochondrial toxicity in PD and other synucleinopathies.
Keywords	electrophysiology ; fluorescence correlation spectroscopy ; hexokinase ; lipids ; metabolites ; mitochondria ; peptides ; therapeutics ; toxicity
Language	English
Dates of publication	2022-07
Size	p. 368.
Publishing place	Springer International Publishing
Document type	Article
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-022-04389-w
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