Structural Basis for Ca2+-regulated Muscle Relaxation at Interaction Sites of Troponin with Actin and Tropomyosin

2005 ◽  
Vol 352 (1) ◽  
pp. 178-201 ◽  
Author(s):  
Kenji Murakami ◽  
Fumiaki Yumoto ◽  
Shin-ya Ohki ◽  
Takuo Yasunaga ◽  
Masaru Tanokura ◽  
...  
Keyword(s):  
Muscle Relaxation ◽  
Structural Basis ◽  
Interaction Sites

scholarly journals 2P156 Structural basis for Ca2+-regulated muscle relaxation at interaction sites of troponin with actin and tropomyosin

2005 ◽  
Vol 45 (supplement) ◽  
pp. S158
Author(s):  
K. Murakami ◽  
F. Yumoto ◽  
S. Ohki ◽  
T. Yasunaga ◽  
M. Tanokura ◽  
...  
Keyword(s):  
Muscle Relaxation ◽  
Structural Basis ◽  
Interaction Sites

scholarly journals MLL1 minimal catalytic complex is a dynamic conformational ensemble susceptible to pharmacological allosteric disruption

2018 ◽  
Author(s):  
Lilia Kaustov ◽  
Alexander Lemak ◽  
Hong Wu ◽  
Marco Faini ◽  
Scott Houliston ◽  
...  
Keyword(s):  
Hybrid Methods ◽  
Structural Basis ◽  
Epigenetic Mark ◽  
Conformational Ensemble ◽  
Interaction Sites ◽  
Catalytic Function ◽  
Individual Interaction ◽  
Mixed Lineage Leukaemia ◽  
Repeat Domain ◽  
Histone H3k4

ABSTRACTHistone H3K4 methylation is an epigenetic mark associated with actively transcribed genes. This modification is catalyzed by the mixed lineage leukaemia (MLL) family of histone methyltransferases including MLL1, MLL2, MLL3, MLL4, SET1A and SET1B. Catalytic activity of MLL proteins is dependent on interactions with additional conserved proteins but the structural basis for subunit assembly and the mechanism of regulation is not well understood. We used a hybrid methods approach to study the assembly and biochemical function of the minimally active MLL1 complex (MLL1, WDR5 and RbBP5). A combination of small angle X-ray scattering (SAXS), cross-linking mass spectrometry (XL-MS), NMR spectroscopy, and computational modeling were used to generate a dynamic ensemble model in which subunits are assembled via multiple weak interaction sites. We identified a new interaction site between the MLL1 SET domain and the WD40 repeat domain of RbBP5, and demonstrate the susceptibility of the catalytic function of the complex to disruption of individual interaction sites.

scholarly journals The MLL1 trimeric catalytic complex is a dynamic conformational ensemble stabilized by multiple weak interactions

2019 ◽  
Author(s):  
Lilia Kaustov ◽  
Alexander Lemak ◽  
Hong Wu ◽  
Marco Faini ◽  
Lixin Fan ◽  
...  
Keyword(s):  
Hybrid Methods ◽  
Weak Interactions ◽  
Structural Basis ◽  
Resonance Spectroscopy ◽  
Epigenetic Mark ◽  
Conformational Ensemble ◽  
Interaction Sites ◽  
Catalytic Function ◽  
Mixed Lineage Leukaemia ◽  
Histone H3k4

Abstract Histone H3K4 methylation is an epigenetic mark associated with actively transcribed genes. This modification is catalyzed by the mixed lineage leukaemia (MLL) family of histone methyltransferases including MLL1, MLL2, MLL3, MLL4, SET1A and SET1B. The catalytic activity of this family is dependent on interactions with additional conserved proteins, but the structural basis for subunit assembly and the mechanism of regulation is not well understood. We used a hybrid methods approach to study the assembly and biochemical function of the minimally active MLL1 complex (MLL1, WDR5 and RbBP5). A combination of small angle X-ray scattering, cross-linking mass spectrometry, nuclear magnetic resonance spectroscopy and computational modeling were used to generate a dynamic ensemble model in which subunits are assembled via multiple weak interaction sites. We identified a new interaction site between the MLL1 SET domain and the WD40 β-propeller domain of RbBP5, and demonstrate the susceptibility of the catalytic function of the complex to disruption of individual interaction sites.

scholarly journals Assembly and cryo-EM structures of RNA-specific measles virus nucleocapsids provide mechanistic insight into paramyxoviral replication

2019 ◽  
Vol 116 (10) ◽  
pp. 4256-4264 ◽  
Author(s):  
Ambroise Desfosses ◽  
Sigrid Milles ◽  
Malene Ringkjøbing Jensen ◽  
Serafima Guseva ◽  
Jacques-Philippe Colletier ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Measles Virus ◽  
Rna Binding ◽  
Structural Basis ◽  
Particle Assembly ◽  
Interaction Sites ◽  
Assembly Kinetics ◽  
High Resolution Structure ◽  
Binding Groove

Assembly of paramyxoviral nucleocapsids on the RNA genome is an essential step in the viral cycle. The structural basis of this process has remained obscure due to the inability to control encapsidation. We used a recently developed approach to assemble measles virus nucleocapsid-like particles on specific sequences of RNA hexamers (poly-Adenine and viral genomic 5′) in vitro, and determined their cryoelectron microscopy maps to 3.3-Å resolution. The structures unambiguously determine 5′ and 3′ binding sites and thereby the binding-register of viral genomic RNA within nucleocapsids. This observation reveals that the 3′ end of the genome is largely exposed in fully assembled measles nucleocapsids. In particular, the final three nucleotides of the genome are rendered accessible to the RNA-dependent RNA polymerase complex, possibly enabling efficient RNA processing. The structures also reveal local and global conformational changes in the nucleoprotein upon assembly, in particular involving helix α6 and helix α13 that form edges of the RNA binding groove. Disorder is observed in the bound RNA, localized at one of the two backbone conformational switch sites. The high-resolution structure allowed us to identify putative nucleobase interaction sites in the RNA-binding groove, whose impact on assembly kinetics was measured using real-time NMR. Mutation of one of these sites, R195, whose sidechain stabilizes both backbone and base of a bound nucleic acid, is thereby shown to be essential for nucleocapsid-like particle assembly.

scholarly journals Sarcoplasmic reticulum–mitochondrial through-space coupling in skeletal muscleThis paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

2009 ◽  
Vol 34 (3) ◽  
pp. 389-395 ◽  
Author(s):  
Robert T. Dirksen
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Calcium Release ◽  
Atp Hydrolysis ◽  
Peer Review Process ◽  
Muscle Relaxation ◽  
Structural Basis ◽  
Atp Production ◽  
Atp Generation ◽  
Selection Of

The skeletal muscle contractile machine is fueled by both calcium and ATP. Calcium ions activate the contractile machinery by binding to troponin C and relieving troponin-tropomyosin inhibition of actinomyosin interaction. ATP binding to myosin during the contractile cycle results in myosin detachment from actin, and energy liberated from subsequent ATP hydrolysis is then used to drive the next contractile cycle. ATP is also used to lower myoplasmic calcium levels during muscle relaxation. Thus, muscle contractility is intimately linked to the proper control of sarcomeric Ca2+ delivery and (or) removal and ATP generation and (or) utilization. In skeletal muscle, the sarcoplasmic reticulum (SR) is the primary regulator of calcium storage, release, and reuptake, while glycolysis and the mitochondria are responsible for cellular ATP production. However, the SR and mitochondrial function in muscle are not independent, as calcium uptake into the mitochondria increases ATP production by stimulating oxidative phosphorylation and mitochondrial ATP production, and production and (or) detoxification of reactive oxygen and nitrogen species (ROS/RNS), in turn, modulates SR calcium release and reuptake. Close spatial Ca2+/ATP/ROS/RNS communication between the SR and mitochondria is facilitated by the structural attachment of mitochondria to the calcium release unit (CRU) by 10 nm of electron-dense tethers. The resultant anchoring of mitochondria to the CRU provides a structural basis for maintaining bidirectional SR–mitochondrial through-space communication during vigorous contraction. This review will consider the degree to which this structural link enables privileged or microdomain communication between the SR and mitochondria in skeletal muscle.

scholarly journals 1P148 Structural basis for Ca^-sensitive muscle relaxation at actin-binding sites of troponin

2004 ◽  
Vol 44 (supplement) ◽  
pp. S66
Author(s):  
K. Murakami ◽  
F. Yumoto ◽  
S. Ohki ◽  
T. Yasunaga ◽  
M. Tanokura ◽  
...  
Keyword(s):  
Binding Sites ◽  
Muscle Relaxation ◽  
Actin Binding ◽  
Structural Basis

scholarly journals Structural Basis of Ligand Interactions of the Large Extracellular Domain of Tetraspanin CD81

2012 ◽  
Vol 86 (18) ◽  
pp. 9606-9616 ◽  
Author(s):  
Sundaresan Rajesh ◽  
Pooja Sridhar ◽  
Birke Andrea Tews ◽  
Lucie Fénéant ◽  
Laurence Cocquerel ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Primary Liver Cancer ◽  
Structural Basis ◽  
Extracellular Loop ◽  
Entry Level ◽  
Interaction Sites ◽  
Loop Region ◽  
Binding Interface ◽  
Ligand Interactions ◽  
Large Extracellular Loop

Hepatitis C virus (HCV) causes chronic liver disease, cirrhosis, and primary liver cancer. Despite 130 million people being at risk worldwide, no vaccine exists, and effective therapy is limited by drug resistance, toxicity, and high costs. The tetraspanin CD81 is an essential entry-level receptor required for HCV infection of hepatocytes and represents a critical target for intervention. In this study, we report the first structural characterization of the large extracellular loop of CD81, expressed in mammalian cells and studied in physiological solutions. The HCV E2 glycoprotein recognizes CD81 through a dynamic loop on the helical bundle, which was shown by nuclear magnetic resonance (NMR) spectroscopy to adopt a conformation distinct from that seen in crystals. A novel membrane binding interface was revealed adjacent to the exposed HCV interaction site in the extracellular loop of CD81. The binding pockets for two proposed inhibitors of the CD81-HCV interaction, namely, benzyl salicylate and fexofenadine, were shown to overlap the HCV and membrane interaction sites. Although the dynamic loop region targeted by these compounds presents challenges for structure-based design, the NMR assignments enable realistic screening and validation of ligands. Together, these data provide an improved avenue for developing potent agents that specifically block CD81-HCV interaction and also pave a way for elucidating the recognition mechanisms of diverse tetraspanins.

scholarly journals TMPs Interaction Domain: A Discovery of Structural Universality Among TMPs Interaction Sites Using Deep Learning Method

2021 ◽  
Author(s):  
Yihang Bao ◽  
Weixi Wang ◽  
Minglong Dong ◽  
Fei He ◽  
Han Wang
Keyword(s):  
Deep Learning ◽  
Drug Targets ◽  
Binding Pocket ◽  
Structural Basis ◽  
Interaction Domain ◽  
Interaction Sites ◽  
Interaction Domains ◽  
Interaction Regions ◽  
Deep Learning Model ◽  
Important Drug

Transmembrane proteins (TMPs) serve as important drug targets and accounts for nearly half of the drugs currently available in the market. Research into TMPs interactions and their structural basis will provide key information for drug research and new drug development. Based on previous works like a binding pocket or binding site, our main purpose in this study is to find whether the structural universality (Interaction Domain) exists in all kinds of TMPs interaction regions through a computational approach. After implementing the experiments using our 3D deep learning model and achieve the Matthews correlation coefficient (MCC) of 0.36, we found strong evidence for the existence of the structural basis among TMPs interaction regions. That means those regions, or we call them interaction domains, are structural specific distinguishing to the domains without any interaction. According to this, this work provides a new theoretical basis for TMPs interaction research and can greatly boost the development of the drug industry.

scholarly journals Myosin-based regulation of twitch and tetanic contractions in mammalian skeletal muscle

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Cameron Hill ◽  
Elisabetta Brunello ◽  
Luca Fusi ◽  
Jesús G Ovejero ◽  
Malcolm Irving
Keyword(s):  
Skeletal Muscle ◽  
Muscle Activation ◽  
Structural Changes ◽  
Muscle Relaxation ◽  
Thick Filament ◽  
Complete Recovery ◽  
Structural Basis ◽  
Mammalian Skeletal Muscle ◽  
Time Resolved ◽  
Single Action

Time-resolved X-ray diffraction from isolated fast-twitch muscles of the mouse was used to show how structural changes in the myosin-containing thick filaments contribute to the regulation of muscle contraction, extending the previous focus on regulation by the actin-containing thin filaments. This study shows that muscle activation involves the following sequence of structural changes: thin filament activation, disruption of the helical array of myosin motors characteristic of resting muscle, release of myosin motor domains from the folded conformation on the filament backbone, and actin attachment. Physiological force generation in the 'twitch' response of skeletal muscle to single action potential stimulation is limited by incomplete activation of the thick filament and the rapid inactivation of both filaments. Muscle relaxation after repetitive stimulation is accompanied by complete recovery of the folded motor conformation on the filament backbone but incomplete reformation of the helical array, revealing a structural basis for post-tetanic potentiation in isolated muscle.

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