The Experts below are selected from a list of 306 Experts worldwide ranked by ideXlab platform
Beate Ditzen - One of the best experts on this subject based on the ideXlab platform.
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Brief psychosocial interventions improve quality of life of patients receiving palliative care: A systematic review and meta-analysis.
Palliative medicine, 2019Co-Authors: Marco Warth, Jens Kessler, Friederike Koehler, Corina Aguilar-raab, Hubert J. Bardenheuer, Beate DitzenAbstract:Background:Patients with a Terminal Disease report a high need for psychosocial and spiritual support. Previous literature reviews on psychosocial interventions in palliative care were restricted t...
Chingchieh Tung - One of the best experts on this subject based on the ideXlab platform.
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The Ryanodine Receptor N-Terminal Disease Hot Spot Intersubunit Interface is Disrupted by Channel Opening and Affected by Disease Mutations Acting via Long-Range Structural Changes
Biophysical Journal, 2012Co-Authors: Lynn Kimlicka, Chingchieh Tung, Kelvin Lau, Filip Van PetegemAbstract:Ryanodine Receptors (RyRs) are intracellular calcium-release channels acting as one of the key regulatory elements in the excitation-contraction coupling. More than 350 mutations have been found in RyRs that are known to underlie severe genetic Diseases. Mutations in the skeletal muscle isoform (RyR1) are associated with malignant hyperthermia (MH) and central core Disease (CCD), while mutations in the cardiac isoform (RyR2) cause catecholaminergic polymorphic ventricular tachycardia (CPVT) and arrhythmogenic right ventricular dysplasia (ARVD). Most mutations confer a gain of function, but the precise mechanisms that explain enhanced channel opening up to the molecular scale have remained elusive. Here we present pseudo-atomic models of the N-Terminal Disease hot spot in the open and closed states of the RyR, along with crystal structures of several Disease mutants. The data show that the intersubunit interfaces formed by tetrameric N-Terminal Disease hot spots are disrupted upon channel opening in wild-type RyRs. This intersubunit interface harbors 19 Disease mutations, the largest cluster within the N-Terminal region, indicating the vulnerability of this interface in channel regulation. We present crystal structures and thermal stabilities of nine Disease mutants located at other interfaces. The effect of most mutations are destabilizing to the protein, with decreases in melting temperatures as large as ∼10°C. Buried Disease mutations cause structural changes to the intersubunit interface, while mutations affecting ionic pairing at the intra-subunit interface significantly alter relative domain orientations. Mutations far away from the intersubunit interface can thus affect these contacts via long-range conformational changes. These results illuminate the intersubunit interface between N-Terminal Disease hot spots as a prime target for Disease mutations through direct or indirect conformational changes.
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the amino Terminal Disease hotspot of ryanodine receptors forms a cytoplasmic vestibule
Nature, 2010Co-Authors: Chingchieh Tung, Lynn Kimlicka, P A Lobo, Filip Van PetegemAbstract:Ryanodine receptors are large ion channels that mediate the release of Ca2+ from the endoplasmic or sarcoplasmic reticulum, and mutations in these receptors can lead to severe genetic conditions in both cardiac and skeletal muscles. The X-ray crystal structure of a type 1 ryanodine receptor is now reported. The exact locations of more than 50 Disease-related mutations have been found in the full-length receptor. The Disease mutations seem to cause misfolding of an individual domain, to destabilize interactions between the three N-Terminal domains, or to otherwise affect one of the other domain interfaces. Mutations in ryanodine receptors can lead to severe genetic conditions in both cardiac and skeletal muscles. These authors report the X-ray crystal structure of a type 1 ryanodine receptor and pinpoint the exact locations of more than 50 Disease-related mutations in the full-length receptor. The Disease mutations seem to cause misfolding of an individual domain, to destabilize interactions between the three amino-Terminal domains, or to otherwise affect one of the other domain interfaces. Many physiological events require transient increases in cytosolic Ca2+ concentrations. Ryanodine receptors (RyRs) are ion channels that govern the release of Ca2+ from the endoplasmic and sarcoplasmic reticulum1. Mutations in RyRs can lead to severe genetic conditions that affect both cardiac and skeletal muscle, but locating the mutated residues in the full-length channel structure has been difficult2,3. Here we show the 2.5 A resolution crystal structure of a region spanning three domains of RyR type 1 (RyR1), encompassing amino acid residues 1–559. The domains interact with each other through a predominantly hydrophilic interface. Docking in RyR1 electron microscopy maps4,5 unambiguously places the domains in the cytoplasmic portion of the channel, forming a 240-kDa cytoplasmic vestibule around the four-fold symmetry axis. We pinpoint the exact locations of more than 50 Disease-associated mutations in full-length RyR1 and RyR2. The mutations can be classified into three groups: those that destabilize the interfaces between the three amino-Terminal domains, disturb the folding of individual domains or affect one of six interfaces with other parts of the receptor. We propose a model whereby the opening of a RyR coincides with allosterically coupled motions within the N-Terminal domains. This process can be affected by mutations that target various interfaces within and across subunits. The crystal structure provides a framework to understand the many Disease-associated mutations in RyRs that have been studied using functional methods, and will be useful for developing new strategies to modulate RyR function in Disease states.
Lynn Kimlicka - One of the best experts on this subject based on the ideXlab platform.
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The Ryanodine Receptor N-Terminal Disease Hot Spot Intersubunit Interface is Disrupted by Channel Opening and Affected by Disease Mutations Acting via Long-Range Structural Changes
Biophysical Journal, 2012Co-Authors: Lynn Kimlicka, Chingchieh Tung, Kelvin Lau, Filip Van PetegemAbstract:Ryanodine Receptors (RyRs) are intracellular calcium-release channels acting as one of the key regulatory elements in the excitation-contraction coupling. More than 350 mutations have been found in RyRs that are known to underlie severe genetic Diseases. Mutations in the skeletal muscle isoform (RyR1) are associated with malignant hyperthermia (MH) and central core Disease (CCD), while mutations in the cardiac isoform (RyR2) cause catecholaminergic polymorphic ventricular tachycardia (CPVT) and arrhythmogenic right ventricular dysplasia (ARVD). Most mutations confer a gain of function, but the precise mechanisms that explain enhanced channel opening up to the molecular scale have remained elusive. Here we present pseudo-atomic models of the N-Terminal Disease hot spot in the open and closed states of the RyR, along with crystal structures of several Disease mutants. The data show that the intersubunit interfaces formed by tetrameric N-Terminal Disease hot spots are disrupted upon channel opening in wild-type RyRs. This intersubunit interface harbors 19 Disease mutations, the largest cluster within the N-Terminal region, indicating the vulnerability of this interface in channel regulation. We present crystal structures and thermal stabilities of nine Disease mutants located at other interfaces. The effect of most mutations are destabilizing to the protein, with decreases in melting temperatures as large as ∼10°C. Buried Disease mutations cause structural changes to the intersubunit interface, while mutations affecting ionic pairing at the intra-subunit interface significantly alter relative domain orientations. Mutations far away from the intersubunit interface can thus affect these contacts via long-range conformational changes. These results illuminate the intersubunit interface between N-Terminal Disease hot spots as a prime target for Disease mutations through direct or indirect conformational changes.
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the amino Terminal Disease hotspot of ryanodine receptors forms a cytoplasmic vestibule
Nature, 2010Co-Authors: Chingchieh Tung, Lynn Kimlicka, P A Lobo, Filip Van PetegemAbstract:Ryanodine receptors are large ion channels that mediate the release of Ca2+ from the endoplasmic or sarcoplasmic reticulum, and mutations in these receptors can lead to severe genetic conditions in both cardiac and skeletal muscles. The X-ray crystal structure of a type 1 ryanodine receptor is now reported. The exact locations of more than 50 Disease-related mutations have been found in the full-length receptor. The Disease mutations seem to cause misfolding of an individual domain, to destabilize interactions between the three N-Terminal domains, or to otherwise affect one of the other domain interfaces. Mutations in ryanodine receptors can lead to severe genetic conditions in both cardiac and skeletal muscles. These authors report the X-ray crystal structure of a type 1 ryanodine receptor and pinpoint the exact locations of more than 50 Disease-related mutations in the full-length receptor. The Disease mutations seem to cause misfolding of an individual domain, to destabilize interactions between the three amino-Terminal domains, or to otherwise affect one of the other domain interfaces. Many physiological events require transient increases in cytosolic Ca2+ concentrations. Ryanodine receptors (RyRs) are ion channels that govern the release of Ca2+ from the endoplasmic and sarcoplasmic reticulum1. Mutations in RyRs can lead to severe genetic conditions that affect both cardiac and skeletal muscle, but locating the mutated residues in the full-length channel structure has been difficult2,3. Here we show the 2.5 A resolution crystal structure of a region spanning three domains of RyR type 1 (RyR1), encompassing amino acid residues 1–559. The domains interact with each other through a predominantly hydrophilic interface. Docking in RyR1 electron microscopy maps4,5 unambiguously places the domains in the cytoplasmic portion of the channel, forming a 240-kDa cytoplasmic vestibule around the four-fold symmetry axis. We pinpoint the exact locations of more than 50 Disease-associated mutations in full-length RyR1 and RyR2. The mutations can be classified into three groups: those that destabilize the interfaces between the three amino-Terminal domains, disturb the folding of individual domains or affect one of six interfaces with other parts of the receptor. We propose a model whereby the opening of a RyR coincides with allosterically coupled motions within the N-Terminal domains. This process can be affected by mutations that target various interfaces within and across subunits. The crystal structure provides a framework to understand the many Disease-associated mutations in RyRs that have been studied using functional methods, and will be useful for developing new strategies to modulate RyR function in Disease states.
Filip Van Petegem - One of the best experts on this subject based on the ideXlab platform.
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Conformational Dynamics Inside Amino-Terminal Disease Hotspot of Ryanodine Receptor
Structure (London England : 1993), 2013Co-Authors: Xiaowei Zhong, Filip Van Petegem, Ying Liu, Li Zhu, Xing Meng, Ruiwu Wang, Terence Wagenknecht, S.r. Wayne Chen, Zheng LiuAbstract:Summary The N-Terminal region of both skeletal and cardiac ryanodine receptor is a Disease mutation hotspot. Recently, a crystal structure of the RyR1 fragment (residues 1–559) was solved. This N-Terminal structure contains three separate domains, A, B, and C, and was docked into a central vestibule in a full-length RyR1 cryo-EM map. Here, we reconstructed three-dimensional cryo-EM structures of two GFP-tagged RyR2s with GFP inserted after residue Glu-310 and Ser-437, respectively. The structures of RyR2 E310-GFP and RyR2 S437-GFP displayed an extra mass on domain B and C, directly validating the predicted docking model. Next, we revealed domain movements in molecular dynamics flexible fitting models in both the closed and open state cryo-EM maps. To further probe the conformational changes, we generated FRET pairs by inserting CFP or YFP in two selected domains, FRET studies of three dual-insertion pairs and three co-expressed single-insertion pairs showed the dynamic structural changes within the N-Terminal domains.
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The Ryanodine Receptor N-Terminal Disease Hot Spot Intersubunit Interface is Disrupted by Channel Opening and Affected by Disease Mutations Acting via Long-Range Structural Changes
Biophysical Journal, 2012Co-Authors: Lynn Kimlicka, Chingchieh Tung, Kelvin Lau, Filip Van PetegemAbstract:Ryanodine Receptors (RyRs) are intracellular calcium-release channels acting as one of the key regulatory elements in the excitation-contraction coupling. More than 350 mutations have been found in RyRs that are known to underlie severe genetic Diseases. Mutations in the skeletal muscle isoform (RyR1) are associated with malignant hyperthermia (MH) and central core Disease (CCD), while mutations in the cardiac isoform (RyR2) cause catecholaminergic polymorphic ventricular tachycardia (CPVT) and arrhythmogenic right ventricular dysplasia (ARVD). Most mutations confer a gain of function, but the precise mechanisms that explain enhanced channel opening up to the molecular scale have remained elusive. Here we present pseudo-atomic models of the N-Terminal Disease hot spot in the open and closed states of the RyR, along with crystal structures of several Disease mutants. The data show that the intersubunit interfaces formed by tetrameric N-Terminal Disease hot spots are disrupted upon channel opening in wild-type RyRs. This intersubunit interface harbors 19 Disease mutations, the largest cluster within the N-Terminal region, indicating the vulnerability of this interface in channel regulation. We present crystal structures and thermal stabilities of nine Disease mutants located at other interfaces. The effect of most mutations are destabilizing to the protein, with decreases in melting temperatures as large as ∼10°C. Buried Disease mutations cause structural changes to the intersubunit interface, while mutations affecting ionic pairing at the intra-subunit interface significantly alter relative domain orientations. Mutations far away from the intersubunit interface can thus affect these contacts via long-range conformational changes. These results illuminate the intersubunit interface between N-Terminal Disease hot spots as a prime target for Disease mutations through direct or indirect conformational changes.
Filip Van Petegem - One of the best experts on this subject based on the ideXlab platform.
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the amino Terminal Disease hotspot of ryanodine receptors forms a cytoplasmic vestibule
Nature, 2010Co-Authors: Chingchieh Tung, Lynn Kimlicka, P A Lobo, Filip Van PetegemAbstract:Ryanodine receptors are large ion channels that mediate the release of Ca2+ from the endoplasmic or sarcoplasmic reticulum, and mutations in these receptors can lead to severe genetic conditions in both cardiac and skeletal muscles. The X-ray crystal structure of a type 1 ryanodine receptor is now reported. The exact locations of more than 50 Disease-related mutations have been found in the full-length receptor. The Disease mutations seem to cause misfolding of an individual domain, to destabilize interactions between the three N-Terminal domains, or to otherwise affect one of the other domain interfaces. Mutations in ryanodine receptors can lead to severe genetic conditions in both cardiac and skeletal muscles. These authors report the X-ray crystal structure of a type 1 ryanodine receptor and pinpoint the exact locations of more than 50 Disease-related mutations in the full-length receptor. The Disease mutations seem to cause misfolding of an individual domain, to destabilize interactions between the three amino-Terminal domains, or to otherwise affect one of the other domain interfaces. Many physiological events require transient increases in cytosolic Ca2+ concentrations. Ryanodine receptors (RyRs) are ion channels that govern the release of Ca2+ from the endoplasmic and sarcoplasmic reticulum1. Mutations in RyRs can lead to severe genetic conditions that affect both cardiac and skeletal muscle, but locating the mutated residues in the full-length channel structure has been difficult2,3. Here we show the 2.5 A resolution crystal structure of a region spanning three domains of RyR type 1 (RyR1), encompassing amino acid residues 1–559. The domains interact with each other through a predominantly hydrophilic interface. Docking in RyR1 electron microscopy maps4,5 unambiguously places the domains in the cytoplasmic portion of the channel, forming a 240-kDa cytoplasmic vestibule around the four-fold symmetry axis. We pinpoint the exact locations of more than 50 Disease-associated mutations in full-length RyR1 and RyR2. The mutations can be classified into three groups: those that destabilize the interfaces between the three amino-Terminal domains, disturb the folding of individual domains or affect one of six interfaces with other parts of the receptor. We propose a model whereby the opening of a RyR coincides with allosterically coupled motions within the N-Terminal domains. This process can be affected by mutations that target various interfaces within and across subunits. The crystal structure provides a framework to understand the many Disease-associated mutations in RyRs that have been studied using functional methods, and will be useful for developing new strategies to modulate RyR function in Disease states.