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Article ; Online: Chloride intracellular channel (CLIC) proteins function as fusogens.

Manori, Bar / Vaknin, Alisa / Vaňková, Pavla / Nitzan, Anat / Zaidel-Bar, Ronen / Man, Petr / Giladi, Moshe / Haitin, Yoni

Nature communications

2024 Volume 15, Issue 1, Page(s) 2085

Abstract: Chloride Intracellular Channel (CLIC) family members uniquely transition between soluble and membrane-associated conformations. Despite decades of extensive functional and structural studies, CLICs' function as ion channels remains debated, rendering our ...

Abstract	Chloride Intracellular Channel (CLIC) family members uniquely transition between soluble and membrane-associated conformations. Despite decades of extensive functional and structural studies, CLICs' function as ion channels remains debated, rendering our understanding of their physiological role incomplete. Here, we expose the function of CLIC5 as a fusogen. We demonstrate that purified CLIC5 directly interacts with the membrane and induces fusion, as reflected by increased liposomal diameter and lipid and content mixing between liposomes. Moreover, we show that this activity is facilitated by acidic pH, a known trigger for CLICs' transition to a membrane-associated conformation, and that increased exposure of the hydrophobic inter-domain interface is crucial for this process. Finally, mutation of a conserved hydrophobic interfacial residue diminishes the fusogenic activity of CLIC5 in vitro and impairs excretory canal extension in C. elegans in vivo. Together, our results unravel the long-sought physiological role of these enigmatic proteins.
MeSH term(s)	Animals ; Chlorides/metabolism ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans/metabolism ; Chloride Channels/metabolism ; Liposomes
Chemical Substances	Chlorides ; Chloride Channels ; Liposomes
Language	English
Publishing date	2024-03-07
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-46301-z
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Structural biology: a 'funny' cyclic dinucleotide receptor.

Haitin, Yoni

Nature chemical biology

2014 Volume 10, Issue 6, Page(s) 413–414

Abstract: Deciphering the molecular basis of HCN channel regulation by cGMP leads to the serendipitous discovery of cyclic dinucleotides as potent inhibitors of I(f) current in the heart. ...

Abstract	Deciphering the molecular basis of HCN channel regulation by cGMP leads to the serendipitous discovery of cyclic dinucleotides as potent inhibitors of I(f) current in the heart.
MeSH term(s)	Animals ; Cyclic AMP/metabolism ; Cyclic GMP/analogs & derivatives ; Cyclic GMP/metabolism ; Dinucleoside Phosphates/metabolism ; Humans ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism ; Ion Channel Gating/physiology ; Muscle Proteins/metabolism ; Potassium Channels/metabolism
Chemical Substances	Dinucleoside Phosphates ; HCN4 protein, human ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ; Muscle Proteins ; Potassium Channels ; cyclic diadenosine phosphate ; bis(3',5')-cyclic diguanylic acid (61093-23-0) ; Cyclic AMP (E0399OZS9N) ; Cyclic GMP (H2D2X058MU)
Language	English
Publishing date	2014-05-16
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2202962-X
ISSN	1552-4469 ; 1552-4450
ISSN (online)	1552-4469
ISSN	1552-4450
DOI	10.1038/nchembio.1530
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Article ; Online: Complex biophysical changes and reduced neuronal firing in an SCN8A variant associated with developmental delay and epilepsy.

Quinn, Shir / Zhang, Nan / Fenton, Timothy A / Brusel, Marina / Muruganandam, Preethi / Peleg, Yoav / Giladi, Moshe / Haitin, Yoni / Lerche, Holger / Bassan, Haim / Liu, Yuanyuan / Ben-Shalom, Roy / Rubinstein, Moran

Biochimica et biophysica acta. Molecular basis of disease

2024 Volume 1870, Issue 5, Page(s) 167127

Abstract: Mutations in the SCN8A gene, encoding the voltage-gated sodium channel ... ...

Abstract	Mutations in the SCN8A gene, encoding the voltage-gated sodium channel Na
Language	English
Publishing date	2024-03-20
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	60-7
ISSN	1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbadis.2024.167127
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Article ; Online: TTYH family members form tetrameric complexes at the cell membrane

Emelia Melvin / Zuzana Kalaninová / Elia Shlush / Petr Man / Moshe Giladi / Yoni Haitin

Communications Biology, Vol 5, Iss 1, Pp 1-

2022 Volume 11

Abstract: Single-molecule microscopy and in situ cross-linking show that the conserved Tweety homolog (TTYH) proteins have an innate tetrameric organization at the cell membrane. ...

Abstract	Single-molecule microscopy and in situ cross-linking show that the conserved Tweety homolog (TTYH) proteins have an innate tetrameric organization at the cell membrane.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-08-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
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Article ; Online: TTYH family members form tetrameric complexes at the cell membrane.

Melvin, Emelia / Kalaninová, Zuzana / Shlush, Elia / Man, Petr / Giladi, Moshe / Haitin, Yoni

Communications biology

2022 Volume 5, Issue 1, Page(s) 886

Abstract: The conserved Tweety homolog (TTYH) family consists of three paralogs in vertebrates, displaying a ubiquitous expression pattern. Although considered as ion channels for almost two decades, recent structural and functional analyses refuted this role. ... ...

Abstract	The conserved Tweety homolog (TTYH) family consists of three paralogs in vertebrates, displaying a ubiquitous expression pattern. Although considered as ion channels for almost two decades, recent structural and functional analyses refuted this role. Intriguingly, while all paralogs shared a dimeric stoichiometry following detergent solubilization, their structures revealed divergence in their relative subunit orientation. Here, we determined the stoichiometry of intact mouse TTYH (mTTYH) complexes in cells. Using cross-linking and single-molecule fluorescence microscopy, we demonstrate that mTTYH1 and mTTYH3 form tetramers at the plasma membrane, stabilized by interactions between their extracellular domains. Using blue-native PAGE, fluorescence-detection size-exclusion chromatography, and hydrogen/deuterium exchange mass spectrometry (HDX-MS), we reveal that detergent solubilization results in tetramers destabilization, leading to their dissolution into dimers. Moreover, HDX-MS demonstrates that the extracellular domains are stabilized in the context of the tetrameric mTTYH complex. Together, our results expose the innate tetrameric organization of TTYH complexes at the cell membrane. Future structural analyses of these assemblies in native membranes are required to illuminate their long-sought cellular function.
MeSH term(s)	Animals ; Cell Membrane ; Detergents ; Hydrogen Deuterium Exchange-Mass Spectrometry ; Mice
Chemical Substances	Detergents
Language	English
Publishing date	2022-08-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-022-03862-3
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Article ; Online: Structure of KCNH2 cyclic nucleotide-binding homology domain reveals a functionally vital salt-bridge.

Ben-Bassat, Ariel / Giladi, Moshe / Haitin, Yoni

The Journal of general physiology

2020 Volume 152, Issue 4

Abstract: Human KCNH2 channels (hKCNH2, ether-à-go-go [EAG]-related gene, hERG) are best known for their contribution to cardiac action potential repolarization and have key roles in various pathologies. Like other KCNH family members, hKCNH2 channels contain a ... ...

Abstract	Human KCNH2 channels (hKCNH2, ether-à-go-go [EAG]-related gene, hERG) are best known for their contribution to cardiac action potential repolarization and have key roles in various pathologies. Like other KCNH family members, hKCNH2 channels contain a unique intracellular complex, consisting of an N-terminal eag domain and a C-terminal cyclic nucleotide-binding homology domain (CNBHD), which is crucial for channel function. Previous studies demonstrated that the CNBHD is occupied by an intrinsic ligand motif, in a self-liganded conformation, providing a structural mechanism for the lack of KCNH channel regulation by cyclic nucleotides. While there have been significant advancements in the structural and functional characterization of the CNBHD of KCNH channels, a high-resolution structure of the hKCNH2 intracellular complex has been missing. Here, we report the 1.5 Å resolution structure of the hKCNH2 channel CNBHD. The structure reveals the canonical fold shared by other KCNH family members, where the spatial organization of the intrinsic ligand is preserved within the β-roll region. Moreover, measurements of small-angle x-ray scattering profile in solution, as well as comparison with a recent NMR analysis of hKCNH2, revealed high agreement with the crystallographic structure, indicating an overall low flexibility in solution. Importantly, we identified a novel salt-bridge (E807-R863) which was not previously resolved in the NMR and cryo-EM structures. Electrophysiological analysis of charge-reversal mutations revealed the bridge's crucial role in hKCNH2 function. Moreover, comparison with other KCNH members revealed the structural conservation of this salt-bridge, consistent with its functional significance. Together with the available structure of the mouse KCNH1 intracellular complex and previous electrophysiological and spectroscopic studies of KCNH family members, we propose that this salt-bridge serves as a strategically positioned linchpin to support both the spatial organization of the intrinsic ligand and the maintenance of the intracellular complex interface.
MeSH term(s)	Amino Acid Sequence ; Animals ; ERG1 Potassium Channel/metabolism ; Humans ; Ligands ; Magnetic Resonance Imaging/methods ; Mice ; Mutation/genetics ; Nucleotides, Cyclic/metabolism ; Protein Binding/physiology ; Sequence Homology ; Xenopus laevis/metabolism
Chemical Substances	ERG1 Potassium Channel ; KCNH2 protein, human ; Ligands ; Nucleotides, Cyclic
Language	English
Publishing date	2020-04-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3118-5
ISSN	1540-7748 ; 0022-1295
ISSN (online)	1540-7748
ISSN	0022-1295
DOI	10.1085/jgp.201912505
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Article ; Online: Conserved cysteine dioxidation enhances membrane interaction of human Cl

Ferofontov, Alisa / Vankova, Pavla / Man, Petr / Giladi, Moshe / Haitin, Yoni

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2020 Volume 34, Issue 8, Page(s) 9925–9940

Abstract: The human chloride intracellular channel (hCLIC) family is thought to transition between globular and membrane-associated forms by exposure of a hydrophobic surface. However, the molecular identity of this surface, and the triggering events leading to ... ...

Abstract	The human chloride intracellular channel (hCLIC) family is thought to transition between globular and membrane-associated forms by exposure of a hydrophobic surface. However, the molecular identity of this surface, and the triggering events leading to its exposure, remain elusive. Here, by combining biochemical and structural approaches, together with mass spectrometry (MS) analyses, we show that hCLIC5 is inherently flexible. X-ray crystallography revealed the existence of a globular conformation, while small-angle X-ray scattering showed additional elongated forms consisting of exposure of the conserved hydrophobic inter-domain interface to the bulk phase. Tryptophan fluorescence measurements demonstrated that the transition to the membrane-associated form is enhanced by the presence of oxidative environment and lipids. Using MS, we identified a dose-dependent oxidation of a highly conserved cysteine residue, known to play a key role in the structurally related omega-class of glutathione-S-transferases. Hydrogen/deuterium exchange MS analysis revealed that oxidation of this cysteine facilitates the exposure of the conserved hydrophobic inter-domain interface. Together, our results pinpoint an oxidation of a specific cysteine residue as a triggering mechanism initializing the molecular commitment for membrane interaction in the CLIC family.
MeSH term(s)	Cell Membrane/metabolism ; Chloride Channels/chemistry ; Chloride Channels/metabolism ; Crystallography, X-Ray ; Cysteine/chemistry ; Cysteine/metabolism ; Humans ; Microfilament Proteins/chemistry ; Microfilament Proteins/metabolism ; Models, Molecular ; Protein Binding ; Protein Conformation
Chemical Substances	CLIC5 protein, human ; Chloride Channels ; Microfilament Proteins ; Cysteine (K848JZ4886)
Language	English
Publishing date	2020-06-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.202000399R
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Zs.A 2266: 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: Ultrasensitive chemiluminescent neuraminidase probe for rapid screening and identification of small-molecules with antiviral activity against influenza A virus in mammalian cells.

Shelef, Omri / Gutkin, Sara / Feder, Daniel / Ben-Bassat, Ariel / Mandelboim, Michal / Haitin, Yoni / Ben-Tal, Nir / Bacharach, Eran / Shabat, Doron

Chemical science

2022 Volume 13, Issue 42, Page(s) 12348–12357

Abstract: Influenza A virus is the most virulent influenza subtype and is associated with large-scale global pandemics characterized by high levels of morbidity and mortality. Developing simple and sensitive molecular methods for detecting influenza viruses is ... ...

Abstract	Influenza A virus is the most virulent influenza subtype and is associated with large-scale global pandemics characterized by high levels of morbidity and mortality. Developing simple and sensitive molecular methods for detecting influenza viruses is critical. Neuraminidase, an exo-glycosidase displayed on the surface of influenza virions, is responsible for the release of the virions and their spread in the infected host. Here, we present a new phenoxy-dioxetane chemiluminescent probe (CLNA) that can directly detect neuraminidase activity. The probe exhibits an effective turn-on response upon reaction with neuraminidase and produces a strong emission signal at 515 nm with an extremely high signal-to-noise ratio. Comparison measurements of our new probe with previously reported analogous neuraminidase optical probes showed superior detection capability in terms of response time and sensitivity. Thus, as far as we know, our probe is the most sensitive neuraminidase probe known to date. The chemiluminescence turn-on response produced by our neuraminidase probe enables rapid screening for small molecules that inhibit viral replication through different mechanisms as validated directly in influenza A-infected mammalian cells using the known inhibitors oseltamivir and amantadine. We expect that our new chemiluminescent neuraminidase probe will prove useful for various applications requiring neuraminidase detection including drug discovery assays against various influenza virus strains in mammalian cells.
Language	English
Publishing date	2022-09-26
Publishing country	England
Document type	Journal Article
ZDB-ID	2559110-1
ISSN	2041-6539 ; 2041-6520
ISSN (online)	2041-6539
ISSN	2041-6520
DOI	10.1039/d2sc03460c
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Article ; Online: Structural basis for long-chain isoprenoid synthesis by

Giladi, Moshe / Lisnyansky Bar-El, Michal / Vaňková, Pavla / Ferofontov, Alisa / Melvin, Emelia / Alkaderi, Suha / Kavan, Daniel / Redko, Boris / Haimov, Elvira / Wiener, Reuven / Man, Petr / Haitin, Yoni

Science advances

2022 Volume 8, Issue 20, Page(s) eabn1171

Abstract: Isoprenoids are synthesized by the prenyltransferase superfamily, which is subdivided according to the product stereoisomerism and length. In short- and medium-chain isoprenoids, product length correlates with active site volume. However, enzymes ... ...

Abstract	Isoprenoids are synthesized by the prenyltransferase superfamily, which is subdivided according to the product stereoisomerism and length. In short- and medium-chain isoprenoids, product length correlates with active site volume. However, enzymes synthesizing long-chain products and rubber synthases fail to conform to this paradigm, because of an unexpectedly small active site. Here, we focused on the human
Language	English
Publishing date	2022-05-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abn1171
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Article ; Online: Allosteric inhibitors targeting the calmodulin-PIP2 interface of SK4 K

Burg, Shira / Shapiro, Shir / Peretz, Asher / Haimov, Elvira / Redko, Boris / Yeheskel, Adva / Simhaev, Luba / Engel, Hamutal / Raveh, Avi / Ben-Bassat, Ariel / Murninkas, Michael / Polak, Rotem / Haitin, Yoni / Etzion, Yoram / Attali, Bernard

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

2022 Volume 119, Issue 34, Page(s) e2202926119

Abstract: ... The ... ...

Abstract	The Ca
MeSH term(s)	Animals ; Atrial Fibrillation/drug therapy ; Calcium Signaling ; Calmodulin/metabolism ; Cryoelectron Microscopy ; Humans ; Intermediate-Conductance Calcium-Activated Potassium Channels/antagonists & inhibitors ; Intermediate-Conductance Calcium-Activated Potassium Channels/metabolism ; Molecular Docking Simulation ; Mutagenesis, Site-Directed ; Phosphatidylinositol 4,5-Diphosphate ; Potassium Channel Blockers/pharmacology ; Rats
Chemical Substances	Calmodulin ; Intermediate-Conductance Calcium-Activated Potassium Channels ; KCNN4 protein, human ; Phosphatidylinositol 4,5-Diphosphate ; Potassium Channel Blockers
Language	English
Publishing date	2022-08-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2202926119
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