scholarly journals Comparative structural analysis of human Nav1.1 and Nav1.5 reveals mutational hotspots for sodium channelopathies

2021 ◽  
Vol 118 (11) ◽  
pp. e2100066118
Author(s):  
Xiaojing Pan ◽  
Zhangqiang Li ◽  
Xueqin Jin ◽  
Yanyu Zhao ◽  
Gaoxingyu Huang ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Electromechanical Coupling ◽  
Structural Integrity ◽  
Therapeutic Interventions ◽  
Missense Mutations ◽  
Disease Mutations ◽  
Mutational Hotspots ◽  
Cardiac Disorders ◽  
Function Relationship ◽  
Pore Domain

Among the nine subtypes of human voltage-gated sodium (Nav) channels, the brain and cardiac isoforms, Nav1.1 and Nav1.5, each carry more than 400 missense mutations respectively associated with epilepsy and cardiac disorders. High-resolution structures are required for structure–function relationship dissection of the disease variants. We report the cryo-EM structures of the full-length human Nav1.1–β4 complex at 3.3 Å resolution here and the Nav1.5-E1784K variant in the accompanying paper. Up to 341 and 261 disease-related missense mutations in Nav1.1 and Nav1.5, respectively, are resolved. Comparative structural analysis reveals several clusters of disease mutations that are common to both Nav1.1 and Nav1.5. Among these, the majority of mutations on the extracellular loops above the pore domain and the supporting segments for the selectivity filter may impair structural integrity, while those on the pore domain and the voltage-sensing domains mostly interfere with electromechanical coupling and fast inactivation. Our systematic structural delineation of these mutations provides important insight into their pathogenic mechanism, which will facilitate the development of precise therapeutic interventions against various sodium channelopathies.

Pitt–Hopkins syndrome: phenotypic and genotypic description of four unrelated patients and structural analysis of corresponding missense mutations

Neurogenetics ◽  
2021 ◽  
Author(s):  
Tingting Zhao ◽  
Georgi Z. Genchev ◽  
Shengnan Wu ◽  
Guangjun Yu ◽  
Hui Lu ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Missense Mutations

scholarly journals Identification of 31 novel mutations in the F8 gene in Spanish hemophilia A patients: structural analysis of 20 missense mutations suggests new intermolecular binding sites

Blood ◽  
2008 ◽  
Vol 111 (7) ◽  
pp. 3468-3478 ◽  
Author(s):  
Adoración Venceslá ◽  
María Ángeles Corral-Rodríguez ◽  
Manel Baena ◽  
Mónica Cornet ◽  
Montserrat Domènech ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Low Density Lipoprotein ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
Missense Mutations ◽  
Factor X ◽  
Novel Mutations ◽  
Large Deletions ◽  
Function Relationship ◽  
The Impact

Abstract Hemophilia A (HA) is an X-linked bleeding disorder caused by a wide variety of mutations in the factor 8 (F8) gene, leading to absent or deficient factor VIII (FVIII). We analyzed the F8 gene of 267 unrelated Spanish patients with HA. After excluding patients with the common intron-1 and intron-22 inversions and large deletions, we detected 137 individuals with small mutations, 31 of which had not been reported previously. Eleven of these were nonsense, frameshift, and splicing mutations, whereas 20 were missense changes. We assessed the impact of the 20 substitutions based on currently available information about FV and FVIII structure and function relationship, including previously reported results of replacements at these and topologically equivalent positions. Although most changes are likely to cause gross structural perturbations and concomitant cofactor instability, p.Ala375Ser is predicted to affect cofactor activation. Finally, 3 further mutations (p.Pro64Arg, p.Gly494Val, and p.Asp2267Gly) appear to affect cofactor interactions with its carrier protein, von Willebrand factor, with the scavenger receptor low-density lipoprotein receptor–related protein (LRP), and/or with the substrate of the FVIIIapi•FIXa (Xase) complex, factor X. Characterization of these novel mutations is important for adequate genetic counseling in HA families, but also contributes to a better understanding of FVIII structure-function relationship.

Structural Analysis of Basal Bodies of The Isolated Oral Apparatus of Tetrahymena Pyriformis

1970 ◽  
Vol 6 (3) ◽  
pp. 679-700
Author(s):  
J. WOLFE
Keyword(s):  
Structural Analysis ◽  
Cell Membrane ◽  
Basal Body ◽  
Structural Integrity ◽  
Tetrahymena Pyriformis ◽  
Basal Plate ◽  
Basal Bodies ◽  
The Third ◽  
Ionic Detergent

The oral apparatus of Tetrahymena pyriformis was isolated using a non-ionic detergent to disrupt the cell membrane. The mouth consists largely of basal bodies and microfilaments. Each basal body is attached to the mouth by a basal plate which is integrated into the meshwork of microfilaments that confers upon the oral apparatus its structural integrity. Each basal body is composed of 9 triplet microtubules. Two of the 3 tubules, subfibres ‘A’ and ‘B’ are composed of filamentous rows of globules with a spacing of 4.5nm. The third tubule, subfibre ‘C’, is only one-third the length of the basal body.

Structure of the human voltage-gated sodium channel Nav1.4 in complex with β1

Science ◽  
2018 ◽  
Vol 362 (6412) ◽  
pp. eaau2486 ◽  
Author(s):  
Xiaojing Pan ◽  
Zhangqiang Li ◽  
Qiang Zhou ◽  
Huaizong Shen ◽  
Kun Wu ◽  
...  
Keyword(s):  
Model Building ◽  
Fast Inactivation ◽  
Potential Generation ◽  
Voltage Gated ◽  
Cryo Electron Microscopy ◽  
Disease Mutations ◽  
Mechanistic Investigation ◽  
Pore Domain ◽  
Blocking Mechanism ◽  
Insight Into

Voltage-gated sodium (Nav) channels, which are responsible for action potential generation, are implicated in many human diseases. Despite decades of rigorous characterization, the lack of a structure of any human Nav channel has hampered mechanistic understanding. Here, we report the cryo–electron microscopy structure of the human Nav1.4-β1 complex at 3.2-Å resolution. Accurate model building was made for the pore domain, the voltage-sensing domains, and the β1 subunit, providing insight into the molecular basis for Na+ permeation and kinetic asymmetry of the four repeats. Structural analysis of reported functional residues and disease mutations corroborates an allosteric blocking mechanism for fast inactivation of Nav channels. The structure provides a path toward mechanistic investigation of Nav channels and drug discovery for Nav channelopathies.

scholarly journals Structural analysis of pathogenic missense mutations in GABRA2 and identification of a novel de novo variant in the desensitization gate

2020 ◽  
Vol 8 (7) ◽  
Author(s):  
Alba Sanchis‐Juan ◽  
Marcia A. Hasenahuer ◽  
James A. Baker ◽  
Amy McTague ◽  
Katy Barwick ◽  
...  
Keyword(s):  
Structural Analysis ◽  
De Novo ◽  
Missense Mutations ◽  
De Novo Variant

scholarly journals Only as strong as the weakest link: structural analysis of the combined effects of elevated temperature and pCO2 on mussel attachment

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Laura A Newcomb ◽  
Matthew N George ◽  
Michael J O’Donnell ◽  
Emily Carrington
Keyword(s):  
Elevated Temperature ◽  
Structural Analysis ◽  
Structural Integrity ◽  
Proximal Region ◽  
Ocean Warming ◽  
Mode Analysis ◽  
Effect Of Temperature ◽  
High Pco2 ◽  
Combined Effects ◽  
Thread Strength

AbstractPredicting how combinations of stressors will affect failure risk is a key challenge for the field of ecomechanics and, more generally, ecophysiology. Environmental conditions often influence the manufacture and durability of biomaterials, inducing structural failure that potentially compromises organismal reproduction, growth, and survival. Species known for tight linkages between structural integrity and survival include bivalve mussels, which produce numerous byssal threads to attach to hard substrate. Among the current environmental threats to marine organisms are ocean warming and acidification. Elevated pCO2 exposure is known to weaken byssal threads by compromising the strength of the adhesive plaque. This study uses structural analysis to evaluate how an additional stressor, elevated temperature, influences byssal thread quality and production. Mussels (Mytilus trossulus) were placed in controlled temperature and pCO2 treatments, and then, newly produced threads were counted and pulled to failure to determine byssus strength. The effects of elevated temperature on mussel attachment were dramatic; mussels produced 60% weaker and 65% fewer threads at 25°C in comparison to 10°C. These effects combine to weaken overall attachment by 64–88% at 25°C. The magnitude of the effect of pCO2 on thread strength was substantially lower than that of temperature and, contrary to our expectations, positive at high pCO2 exposure. Failure mode analysis localized the effect of temperature to the proximal region of the thread, whereas pCO2 affected only the adhesive plaques. The two stressors therefore act independently, and because their respective target regions are interconnected (resisting tension in series), their combined effects on thread strength are exactly equal to the effect of the strongest stressor. Altogether, these results show that mussels, and the coastal communities they support, may be more vulnerable to the negative effects of ocean warming than ocean acidification.

scholarly journals Interfacial gating triad is crucial for electromechanical transduction in voltage-activated potassium channels

2014 ◽  
Vol 144 (5) ◽  
pp. 457-467 ◽  
Author(s):  
Sandipan Chowdhury ◽  
Benjamin M. Haehnel ◽  
Baron Chanda
Keyword(s):  
Potassium Channels ◽  
Conformational Changes ◽  
Electromechanical Coupling ◽  
Structural Integrity ◽  
Voltage Sensor ◽  
Amino Acid Residues ◽  
Kv Channel ◽  
Electromechanical Transduction ◽  
Voltage Dependent ◽  
Graph Theoretical Approach

Voltage-dependent potassium channels play a crucial role in electrical excitability and cellular signaling by regulating potassium ion flux across membranes. Movement of charged residues in the voltage-sensing domain leads to a series of conformational changes that culminate in channel opening in response to changes in membrane potential. However, the molecular machinery that relays these conformational changes from voltage sensor to the pore is not well understood. Here we use generalized interaction-energy analysis (GIA) to estimate the strength of site-specific interactions between amino acid residues putatively involved in the electromechanical coupling of the voltage sensor and pore in the outwardly rectifying KV channel. We identified candidate interactors at the interface between the S4–S5 linker and the pore domain using a structure-guided graph theoretical approach that revealed clusters of conserved and closely packed residues. One such cluster, located at the intracellular intersubunit interface, comprises three residues (arginine 394, glutamate 395, and tyrosine 485) that interact with each other. The calculated interaction energies were 3–5 kcal, which is especially notable given that the net free-energy change during activation of the Shaker KV channel is ∼14 kcal. We find that this triad is delicately maintained by balance of interactions that are responsible for structural integrity of the intersubunit interface while maintaining sufficient flexibility at a critical gating hinge for optimal transmission of force to the pore gate.

Structural Analysis for a Panamax Bulk Carrier

2008 ◽  
Author(s):  
Sandita Pacuraru-Popoiu ◽  
Paulina Iancu ◽  
Liviu I. Crudu
Keyword(s):  
Structural Analysis ◽  
Stress Distribution ◽  
Structural Integrity ◽  
Dynamic Pressure ◽  
Uniform Structure ◽  
Bulk Carrier ◽  
Element Analysis ◽  
Hull Girder ◽  
Fine Mesh ◽  
Hull Structure

This paper is devoted to the development of a structural analysis for a bulk carrier vessel. According to the CSR requirements for bulk carriers, an assessment of the hull structure using FEA (Finite Element Analysis) on a model extended over 3 cargo holds is presented. This method is used in order to assess the structural integrity of the cargo holds under the considered loads. The selected vessel is a PANAMAX bulk carrier with double hull and longitudinal uniform structure. There are three main priorities for the FE-analysis: one is to perform a fine mesh necessary to capture the stressed induced by the considered loads. The second priority is to apply the right boundary conditions in order to approach the hull girder bending and stress distribution on the cargo holds. The stress distribution is induced by the cargo weight, the hydrostatic pressure and the external water considered as dynamic pressure. The dynamic pressure was computed using an in-house code, neglecting the inertia forces induced by the ship motions and the horizontal accelerations. Also shear forces and bending moments were obtained for head angles of 0, 45 and 180 degrees.

Collagen Network Architecture Varies Between Pure Collagen and Collagen-Fibrin Co-Gels

2012 ◽  
Author(s):  
Victor K. Lai ◽  
Allan M. Kerandi ◽  
Spencer P. Lake ◽  
Robert T. Tranquillo ◽  
Victor H. Barocas
Keyword(s):  
Mechanical Behavior ◽  
Network Architecture ◽  
Rational Design ◽  
Structural Integrity ◽  
Collagen Network ◽  
Fibrin Gel ◽  
Ecm Proteins ◽  
Fibrin Networks ◽  
Pure Collagen ◽  
Function Relationship

Naturally-occurring extracellular matrix (ECM) proteins, e.g. collagen I and fibrin, play an important role in tissues, conferring structural integrity and providing a biochemical environment for eliciting important cellular responses (e.g. migration). Tissue engineers use a variety of matrix polymers as initial scaffolds for seeding cells, sometimes in combination with one another (e.g. collagen-fibrin [1]). For example, our group fabricates arterial tissue equivalents (TEs) by seeding cells in a fibrin gel, which is gradually degraded over time and replaced by cell-produced collagen [2]. While the structure and mechanics of individual ECM proteins have been studied extensively, how multiple fibrillar networks interact to confer overall mechanical behavior remains poorly understood. Narrowing this gap in knowledge of scaffolds comprising multiple fibril networks is crucial in allowing for more rational design in tissue engineering, as cells react differently according to their mechanical environments. For collagen-fibrin networks in particular, early efforts in elucidating interactions between these two fibril networks in co-gels have proven inconclusive due to inconsistent findings from various groups. Recent modeling efforts by our group have shown that simple “series” and “parallel” type interactions provide bounds for the mechanical behavior of collagen-fibrin co-gels [3]. In addition, experiments on pure collagen and fibrin vs. their respective networks from collagen-fibrin co-gels after digestion showed slight differences in mechanical behavior [4]. These previous studies have focused on the composition-function relationship between collagen and fibrin. The objective of the current work is to explore how collagen network architecture changes in the presence of the fibrin network in collagen-fibrin co-gels, thereby providing an added dimension to our understanding of collagen-fibrin systems by elucidating structure-composition-function relationships between collagen and fibrin.

Update of the spectrum of mucopolysaccharidoses type III in Tunisia: identification of three novel mutations and in silico structural analysis of the missense mutations

2017 ◽  
Vol 13 (4) ◽  
pp. 374-380 ◽  
Author(s):  
Souad Ouesleti ◽  
Maria Francisca Coutinho ◽  
Isaura Ribeiro ◽  
Abdehedi Miled ◽  
Dalila Saidane Mosbahi ◽  
...  
Keyword(s):  
Structural Analysis ◽  
In Silico ◽  
Missense Mutations ◽  
Novel Mutations ◽  
Type Iii
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