A 3D cellular context for the macromolecular world

Patwardhan, Ardan; Ashton, Alun; Brandt, Robert; Butcher, Sarah J.; Carzaniga, Raffaella; Chiu, Wah; Collinson, Lucy M.; Doux, Pascal; Duke, Elizabeth; Ellisman, Mark H.; Franken, Erik; Grünewald, Kay; Hériché, Jean‐Karim; Koster, Abraham J.; Kühlbrandt, Werner; Lagerstedt, Ingvar; Larabell, Carolyn A.; Lawson, Catherine L.; Saibil, Helen R.; Sanz-García, Eduardo; Subramaniam, Sriram; Verkade, Paul; Swedlow, Jason R.; Kleywegt, Gerard J.

doi:10.1038/nsmb.2897

Cited by 49 publications

(39 citation statements)

References 33 publications

(34 reference statements)

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“…2 As such, they are essential to the proper functioning of all cellular processes, including metabolism, cell signaling, gene expression, trafficking, cell cycle regulation and the formation of subcellular structures. 3, 4 In the cardiac myocyte, macromolecular complexes also play crucial roles in converting energy, generating and propagating electrical signals and mediating contractility, as well intercellular communication.…”

Section: Introductionmentioning

confidence: 99%

Ion Channel Macromolecular Complexes in Cardiomyocytes: Roles in Sudden Cardiac Death

Abriel

Rougier

Jalife

2015

Circulation Research

124

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The movement of ions across specific channels embedded on the membrane of individual cardiomyocytes is crucial for the generation and propagation of the cardiac electrical impulse. Emerging evidence over the last 20 years strongly suggests that the normal electrical function of the heart is the result of dynamic interactions of membrane ion channels working in an orchestrated fashion as part of complex molecular networks. Such networks work together with exquisite temporal precision to generate each action potential and contraction. Macromolecular complexes play crucial roles in transcription, translation, oligomerization, trafficking, membrane retention, glycosylation, posttranslational modification, turnover, function and degradation of all cardiac ion channels known to date. In addition, the accurate timing of each cardiac beat and contraction demands, a comparable precision on the assembly and organizations of sodium, calcium and potassium channel complexes within specific subcellular microdomains, where physical proximity allows for prompt and efficient interaction. This review article, part of the Compendium on Sudden Cardiac Death, discusses the major issues related to the role of ion channel macromolecular assemblies in normal cardiac electrical function and the mechanisms of arrhythmias leading to sudden cardiac death. It provides an idea of how these issues are being addressed in the laboratory and in the clinic, which important questions remain unanswered, and what future research will be needed to improve knowledge and advance therapy.

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Section: Introductionmentioning

confidence: 99%

Ion Channel Macromolecular Complexes in Cardiomyocytes: Roles in Sudden Cardiac Death

Abriel

Rougier

Jalife

2015

Circulation Research

124

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“…SXT uses the inherent contrast of fully hydrated specimens by imaging in the 'water window' (2.4 nm wavelength, 517 eV) where common biological elements such as carbon and nitrogen absorb X-rays and are therefore visible, whereas water is relatively transparent Larabell and Nugent, 2010;Le Gros et al, 2005;Patwardhan et al, 2014). Additionally, owing to the use of a thin-walled glass capillary tube to flash freeze and image the specimen, there is no visible radiation damage at the achievable resolution, and it is possible to collect projection image tilt series of 180°or greater allowing for a three-dimensional reconstruction with no distortions due to missing wedge artifacts as in electron microscopy (Larabell and Nugent, 2010;Le Gros et al, 2005Parkinson et al, 2008).…”

Section: Sxt Of Sickled Rbcsmentioning

confidence: 99%

Visualizing red blood cell sickling and the effects of inhibition of sphingosine kinase 1 using soft X-ray tomography

Darrow

Zhang

Cinquin

et al. 2016

Journal of Cell Science

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Sickle cell disease is a destructive genetic disorder characterized by the formation of fibrils of deoxygenated hemoglobin, leading to the red blood cell (RBC) morphology changes that underlie the clinical manifestations of this disease. Using cryogenic soft X-ray tomography (SXT), we characterized the morphology of sickled RBCs in terms of volume and the number of protrusions per cell. We were able to identify statistically a relationship between the number of protrusions and the volume of the cell, which is known to correlate to the severity of sickling. This structural polymorphism allows for the classification of the stages of the sickling process. Recent studies have shown that elevated sphingosine kinase 1 (Sphk1)-mediated sphingosine 1-phosphate production contributes to sickling. Here, we further demonstrate that compound 5C, an inhibitor of Sphk1, has anti-sickling properties. Additionally, the variation in cellular morphology upon treatment suggests that this drug acts to delay the sickling process. SXT is an effective tool that can be used to identify the morphology of the sickling process and assess the effectiveness of potential therapeutics.

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“…After consultations with the molecular and cellular 3D bioimaging community in a series of workshops [21], a strong recommendation from the field was to establish an archive where the raw experimental data from cryo-EM (mostly 2D images and movies) could be stored. In response to this, the Electron Microscopy Public Image Archive (EMPIAR) was established at EMBL-EBI in 2014 [9].…”

Section: Structural Biology Archives and What They Have To Offermentioning

confidence: 99%

Structural biology data archiving – where we are and what lies ahead

2018

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For almost 50 years, structural biology has endeavoured to conserve and share its experimental data and their interpretations (usually, atomistic models) through global public archives such as the Protein Data Bank, Electron Microscopy Data Bank and Biological Magnetic Resonance Data Bank (BMRB). These archives are treasure troves of freely accessible data that document our quest for molecular or atomic understanding of biological function and processes in health and disease. They have prepared the field to tackle new archiving challenges as more and more (combinations of) techniques are being utilized to elucidate structure at ever increasing length scales. Furthermore, the field has made substantial efforts to develop validation methods that help users to assess the reliability of structures and to identify the most appropriate data for their needs. In this Review, we present an overview of public data archives in structural biology and discuss the importance of validation for users and producers of structural data. Finally, we sketch our efforts to integrate structural data with bioimaging data and with other sources of biological data. This will make relevant structural information available and more easily discoverable for a wide range of scientists.

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A 3D cellular context for the macromolecular world

Cited by 49 publications

References 33 publications

Ion Channel Macromolecular Complexes in Cardiomyocytes: Roles in Sudden Cardiac Death

Ion Channel Macromolecular Complexes in Cardiomyocytes: Roles in Sudden Cardiac Death

Visualizing red blood cell sickling and the effects of inhibition of sphingosine kinase 1 using soft X-ray tomography

Structural biology data archiving – where we are and what lies ahead

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