Structural Basis for Calcium-Regulated Relaxation of Striated Muscles at Interaction Sites of Troponin with Actin and Tropomyosin

2007 ◽  
pp. 71-86 ◽  
Author(s):  
Kenji Murakami ◽  
Fumiaki Yumoto ◽  
Shin-ya Ohki ◽  
Takuo Yasunaga ◽  
Masaru Tanokura ◽  
...  
Keyword(s):  
Structural Basis ◽  
Striated Muscles ◽  
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.

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 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 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

Organization of tight junctions in the choroid plexus epithelium

1978 ◽  
Vol 36 (2) ◽  
pp. 336-337
Author(s):  
B. Van Deurs ◽  
J. K. Koehler
Keyword(s):  
Choroid Plexus ◽  
Present Report ◽  
Freeze Fracture ◽  
Barrier Properties ◽  
Cell Junctions ◽  
Structural Basis ◽  
Apical Surface ◽  
Choroid Plexus Epithelium ◽  
Solid Nitrogen ◽  
Special Composition

The choroid plexus epithelium constitutes a blood-cerebrospinal fluid (CSF) barrier, and is involved in regulation of the special composition of the CSF. The epithelium is provided with an ouabain-sensitive Na/K-pump located at the apical surface, actively pumping ions into the CSF. The choroid plexus epithelium has been described as “leaky” with a low transepithelial resistance, and a passive transepithelial flux following a paracellular route (intercellular spaces and cell junctions) also takes place. The present report describes the structural basis for these “barrier” properties of the choroid plexus epithelium as revealed by freeze fracture.Choroid plexus from the lateral, third and fourth ventricles of rats were used. The tissue was fixed in glutaraldehyde and stored in 30% glycerol. Freezing was performed either in liquid nitrogen-cooled Freon 22, or directly in a mixture of liquid and solid nitrogen prepared in a special vacuum chamber. The latter method was always used, and considered necessary, when preparations of complementary (double) replicas were made.

Distribution of c-protein isoforms in sarcomeres of developing chick skeletal muscle

1988 ◽  
Vol 46 ◽  
pp. 226-227
Author(s):  
D. A. Fischman ◽  
J. E. Dennis ◽  
T. Obinata ◽  
H. Takano-Ohmuro
Keyword(s):  
Skeletal Muscles ◽  
Thick Filament ◽  
Protein Isoforms ◽  
Actin Binding ◽  
Striated Muscles ◽  
C Protein ◽  
Sarcomeric Protein ◽  
Thick Filaments ◽  
Cross Bridges ◽  
Bridge Bearing

C-protein is a 150 kDa protein found within the A bands of all vertebrate cross-striated muscles. By immunoelectron microscopy, it has been demonstrated that C-protein is distributed along a series of 7-9 transverse stripes in the medial, cross-bridge bearing zone of each A band. This zone is now termed the C-zone of the sarcomere. Interest in this protein has been sparked by its striking distribution in the sarcomere: the transverse repeat between C-protein stripes is 43 nm, almost exactly 3 times the 14.3 nm axial repeat of myosin cross-bridges along the thick filaments. The precise packing of C-protein in the thick filament is still unknown. It is the only sarcomeric protein which binds to both myosin and actin, and the actin-binding is Ca-sensitive. In cardiac and slow, but not fast, skeletal muscles C-protein is phosphorylated. Amino acid composition suggests a protein of little or no αhelical content. Variant forms (isoforms) of C-protein have been identified in cardiac, slow and embryonic muscles.

High resolution spot scan imaging of frozen, hydrated actin bundles with 400kV electrons

1992 ◽  
Vol 50 (1) ◽  
pp. 512-513
Author(s):  
J. Jakana ◽  
M.F. Schmid ◽  
P. Matsudaira ◽  
W. Chiu
Keyword(s):  
High Resolution ◽  
Binding Proteins ◽  
Actin Binding ◽  
Eukaryotic Cells ◽  
Dimensional Structure ◽  
Structural Basis ◽  
Actin Bundle ◽  
Actin Bundles ◽  
3 Dimensional ◽  
Macromolecular Assembly

Actin is a protein found in all eukaryotic cells. In its polymerized form, the cells use it for motility, cytokinesis and for cytoskeletal support. An example of this latter class is the actin bundle in the acrosomal process from the Limulus sperm. The different functions actin performs seem to arise from its interaction with the actin binding proteins. A 3-dimensional structure of this macromolecular assembly is essential to provide a structural basis for understanding this interaction in relationship to its development and functions.

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