A5033746668- Connexins and lens biology
- Yersinia bacterium, plague, ectoparasites research
- Heat shock proteins research
- Protein Kinase Regulation and GTPase Signaling
- Receptor Mechanisms and Signaling
- Nicotinic Acetylcholine Receptors Study
- Hereditary Neurological Disorders
- Ion channel regulation and function
- Bacillus and Francisella bacterial research
- Cellular transport and secretion
- Healthcare and Venom Research
- Monoclonal and Polyclonal Antibodies Research
ETH Zurich
2022-2024
Paul Scherrer Institute
2021-2024
Institute of Molecular Biology and Biophysics
2023
Abstract Adenylyl cyclase 9 (AC9) is a membrane-bound enzyme that converts ATP into cAMP. The weakly activated by forskolin, fully the G protein Gαs subunit and autoinhibited AC9 C-terminus. Although our recent structural studies of AC9-Gαs complex provided framework for understanding autoinhibition, conformational changes undergoes in response to activator binding remains poorly understood. Here, we present cryo-EM structures several distinct states: (i) bound nucleotide inhibitor MANT-GTP,...
Gap junction channels (GJCs) mediate intercellular communication by connecting two neighbouring cells and enabling direct exchange of ions small molecules. Cell coupling via connexin-43 (Cx43) GJCs is important in a wide range cellular processes health disease (Churko Laird, 2013; Liang et al., 2020; Poelzing Rosenbaum, 2004), yet the structural basis Cx43 function regulation has not been determined until now. Here, we describe structure human GJC solved cryo-EM single particle analysis at...
Gap junction channels (GJCs) mediate intercellular communication by connecting two neighbouring cells and enabling direct exchange of ions small molecules. Cell coupling via connexin-43 (Cx43) GJCs is important in a wide range cellular processes health disease (Churko Laird, 2013; Liang et al., 2020; Poelzing Rosenbaum, 2004), yet the structural basis Cx43 function regulation has not been determined until now. Here, we describe structure human GJC solved cryo-EM single particle analysis at...
Abstract Membrane adenylyl cyclase AC8 is regulated by G proteins and calmodulin (CaM), mediating the crosstalk between cAMP pathway Ca 2+ signalling. Despite importance of in physiology, structural basis its regulation CaM not well defined. Here, we report 3.5 Å resolution cryo-EM structure bovine bound to stimulatory Gαs protein presence /CaM. The reveals architecture ordered domains small molecule activator forskolin. extracellular surface features a negatively charged pocket, potential...
In myelinating Schwann cells, connection between myelin layers is mediated by gap junction channels (GJCs) formed docked connexin 32 (Cx32) hemichannels (HCs). Mutations in Cx32 cause the X-linked Charcot-Marie-Tooth disease (CMT1X), a degenerative neuropathy without cure. A molecular link dysfunction and CMT1X pathogenesis still missing. Here, we describe high-resolution cryo-electron microscopy (cryo-EM) structures of GJC HC, along with two CMT1X-linked mutants, W3S R22G. While wild-type...
Connexin gap junction channels (GJCs) are a family of proteins that connect the cytoplasms two neighbouring cells and allow direct intercellular exchange solutes smaller than ~1 kDa, ensuring metabolic electrical coupling tissues. Connexin-32 (Cx32) GJCs mediate in variety tissues, specifically myelinating Schwann cells. Mutations Cx32, such as W3S, associated with peripheral neuropathy, X-linked Charcot-Marie-Tooth (CMT1X) disease. Phospholipids sterols have been shown to regulate...
Abstract Gap junction channels (GJCs) mediate intercellular communication by connecting two neighboring cells and enabling direct exchange of ions small molecules. Cell coupling via connexin-43 (Cx43) GJCs is important in a wide range cellular processes health disease 1-3 , yet the structural basis Cx43 function regulation has not been determined until now. Here we describe structure human GJC solved cryo-EM single particle analysis at 2.26 Å resolution. The pore region features several...
Abstract Membrane adenylyl cyclase AC8 is regulated by G proteins and calmodulin (CaM), mediating the crosstalk between cAMP pathway Ca 2+ signalling. Despite importance of in physiology, including cognitive functions memory, structural basis its regulation CaM not well defined. Here we report 3.5 Å resolution cryo-EM structure bovine bound to /CaM stimulatory Gαs protein. The reveals architecture ordered domains a small molecule activator forskolin. extracellular surface features negatively...
Abstract Connexin gap junction channels and hemichannels play important roles in intercellular communication signaling. Some of connexin isoforms are associated with diseases, including hereditary neuropathies, heart disease cancer. Although small molecule inhibitors connexins show promise as therapeutic agents, the molecular mechanisms channel inhibition unknown. Here, we report cryo-EM structure connexin-36 (Cx36) bound to an anti-malarial drug mefloquine at 2.1 Å resolution. Six binding...
Abstract Gap junction intercellular communication (GJIC) between two adjacent cells involves direct exchange of cytosolic ions and small molecules via connexin gap channels (GJCs). Connexin GJCs have emerged as drug targets, with molecule inhibitors considered a viable therapeutic strategy in several diseases. The molecular mechanisms GJC inhibition by known remain unknown, preventing the development more potent connexin-specific therapeutics. Here we show that inhibitors, mefloquine (MFQ)...
Abstract In myelinating Schwann cells, communication between myelin layers is mediated by gap junction channels (GJC) formed docked connexin 32 hemichannels (HCs). Mutations in Cx32 cause the X-linked Charcot–Marie–Tooth disease (CMT1X), a degenerative neuropathy with no cure. A molecular link dysfunction and CMT1X pathogenesis still missing. Here, we describe high resolution cryo-EM structures of GJC HC, along two CMT1X-linked mutants, W3S R22G. While wild-type mutant GJCs are virtually...
Gap junction channels (GJCs) mediate intercellular communication by connecting two neighboring cells and enabling direct exchange of ions small molecules. Cell coupling via connexin-43 (Cx43) GJCs is important in a wide range cellular processes health disease 1-3 , yet the structural basis Cx43 function regulation has not been determined until now. Here we describe structure human GJC solved cryo-EM single particle analysis at 2.26 Å resolution. The pore region features several lipid-like...
Gap junction intercellular communication (GJIC) between two adjacent cells involves direct exchange of cytosolic ions and small molecules via connexin gap channels (GJCs). Connexin GJCs have emerged as drug targets, with molecule inhibitors considered a viable therapeutic strategy in several diseases. The molecular mechanisms GJC inhibition by known remain unknown, preventing the development more potent connexin-specific therapeutics. Here we show that inhibitors, mefloquine (MFQ)...
Gap junction channels (GJCs) mediate intercellular communication by connecting two neighboring cells and enabling direct exchange of ions small molecules. Cell coupling via connexin-43 (Cx43) GJCs is important in a wide range cellular processes health disease 1-3 , yet the structural basis Cx43 function regulation has not been determined until now. Here we describe structure human GJC solved cryo-EM single particle analysis at 2.26 Å resolution. The pore region features several lipid-like...
Abstract Adenylyl cyclase 9 (AC9) is a membrane-bound enzyme that converts ATP into cAMP. The weakly activated by forskolin, fully the G protein Gαs subunit and autoinhibited AC9 C-terminus. Although our recent structural studies of AC9-Gαs complex provided framework for understanding autoinhibition, conformational changes undergoes in response to activator binding remains poorly understood. Here, we present cryo-EM structures several distinct states: (i) bound nucleotide inhibitor MANT-GTP,...