Effects of myosin variants on interacting-heads motif explain distinct hypertrophic and dilated cardiomyopathy phenotypes

Effects of myosin variants on interacting-heads motif explain distinct hypertrophic and dilated cardiomyopathy phenotypes

Lorenzo Alamo1, James S. Ware2,3,4, Antonio Pinto1, Richard E Gillilan5, Jonathan G. Seidman4, Christine E. Seidman4,6 & Raúl Padrón1

1Centro de Biología Estructural “Humberto Fernández-Morán”, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela; 2National Heart and Lung Institute and MRC London Institute for Medical Sciences, Imperial College London, London, United Kingdom; 3NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London, United Kingdom; 4Department of Genetics, Harvard Medical School, Boston, United States; 5Macromolecular Diffraction Facility, Cornell High Energy Synchrotron Source, Ithaca, United States; 6Cardiovascular Division, Brigham and Women’s Hospital and Howard Hughes Medical Institute, Boston, United States

Email: raul.padron@gmail.com   Padrón lab: http://www.raul-padron.org/lab/

Abstract:  Cardiac b-myosin variants cause hypertrophic (HCM) or dilated (DCM) cardiomyopathy by disrupting sarcomere contraction and relaxation. The locations of variants on isolated myosin head structures predict contractility effects but not the prominent relaxation and energetic deficits that characterize HCM. During relaxation, pairs of myosins form interacting-heads motif (IHM) structures that with other sarcomere proteins establish an energy-saving, super-relaxed (SRX) state. Using a human b-cardiac myosin IHM quasi-atomic model (PDB 5TBY), we defined interactions sites between adjacent myosin heads and associated protein partners, and then analyzed rare variants from 6112 HCM and 1315 DCM patients and 33,370 ExAC controls. HCM variants, 72% that changed electrostatic charges, disproportionately altered IHM interaction residues (expected 23%; HCM 54%, p=2.6×10-19; DCM 26%, p=0.66; controls 20%, p=0.23). HCM variant locations predict impaired IHM formation and stability, and attenuation of the SRX state – accounting for altered contractility, reduced diastolic relaxation, and increased energy consumption, that fully characterizes HCM pathogenesis.

eLife 2017;6:e24634 https://elifesciences.org/articles/24634  doi: 10.7554/eLife.24634

Article PDF download: file elife-24634-figures-v1.pdf Figures PDF download: elife-24634-v1.pdf

Graphical summary: graphical_summary.jpg Top row: Sections of relaxed healthy, HCM and DCM hearts. Bottom row: Human beta-cardiac myosin interacting heads motif (IHM) PDB 5TBY (left) showing the impact of DCM (center) and HCM (right) variants (color spheres) on the IHM structure. Code to reproduce analyses presented in Alamo et al, eLife 2017: https://github.com/jamesware/eLife_Alamo2017

Human beta-cardiac myosin interacting heads motif (IHM) PDB 5TBY:

RCSB Protein Data Bank: http://www.rcsb.org/pdb/explore/structureCluster.do?structureId=5TBY

Protein Data bank in Europe: https://www.ebi.ac.uk/pdbe/entry/pdb/5tby

3D_EM Data Navigator: https://pdbj.org/emnavi/emnavi_detail.php?lgc=1&id=5tby

Yorodumi: https://pdbj.org/emnavi/quick.php?id=pdb-5tby

Spider proteins offer new insight into human heart conditions (Imperial College News)  by Ryan O´Hare

Lessons from a Tarantula: Spider muscles reveals details about mutations that disrupt heart relaxation (Harvard Medical School News)   by Hanae Armitage

Lessons the Tarantula: Spider muscles reveals details about mutations that disrupt heart relaxation (HHMI News) by Hanae Armitage

Descargar trabajo completo: Raul Padron Life

A Latin American Perspective on G Protein–Coupled Receptors

A Latin American Perspective on G Protein–Coupled Receptors

André S. Pupo and J. Adolfo García-Sáinz

Department of Pharmacology, Instituto de Biociências, Universidade Estadual Paulista, Botucatu, São Paulo, Brazil (A.S.P.); and
Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico (J.A.G.-S.)
Received July 8, 2016; accepted August 25, 2016

 

ABSTRACT

G protein–coupled receptors are sensors that interact with a large variety of elements, including photons, ions, and large proteins. Not surprisingly, these receptors participate in the numerous normal physiologic processes that we refer to ashealth and in its perturbations that constitute disease. It has been estimated that a large percentage of drugs currently used in therapeutics target these proteins, and this percentage is larger when illegal drugs are included. The state of the art in this field can be defined with the oxymoron “constant change,” and enormous progress has been made in recent years. A group of scientists working in Latin America were invited to contribute minireviews for this special section to present some of the work performed in this geographical region and foster further international collaboration.

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A Latin American Perspective on Ion Channels

A Latin American Perspective on Ion Channels

Ana Belén Elgoyhen and Carlos Barajas-López

Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, “Héctor N Torres,” Consejo Nacional de Investigaciones Científicas y Técnicas and Instituto de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina (A.B.E.), and División de Biología Molecular, Instituto Potosino de Investigación Científica y Tecnológica, México (C.B.-L.) Received June 6, 2016; accepted July 8, 2016

ABSTRACT

Ion channels, both ligand- and voltage-gated, play fundamental roles in many physiologic processes. Alteration in ion channel function underlies numerous pathologies, including hypertension, diabetes, chronic pain, epilepsy, certain cancers, and neuromuscular diseases. In addition, an increasing number of inherited and de novo ion channel mutations have been shown to contribute to disease states. Ion channels are thus a major class of pharmacotherapeutic targets.

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Francisco J Barrantes. Pontificia Universidad Católica Argentina. Instituto de Investigaciones Biomédicas. Buenos Aires

Francisco J Barrantes. Pontificia Universidad Católica Argentina. Instituto de Investigaciones Biomédicas. Buenos Aires

francisco-barrantesLínea de investigación.Comprender la función sináptica y sus alteraciones (“sinaptopatías”) presentes en muchas enfermedades neurológicas y neuropsiquiátricas es una de las claves para descifrar los mecanismos que operan en la estructura más compleja de la Naturaleza, el cerebro. El objetivo general de investigación de nuestro grupo es, precisamente, aclarar algunos aspectos fundamentales de la función sináptica mediante un enfoque multidisciplinario, desde la molécula hasta el organismo vivo. Para tal fin se emplean a diversas metodologías, incluyendo biología molecular y celular, bioquímica e innovadoras técnicas de microscopía de superresolución (“nanoscopías”). Nuestras investigaciones ponen especial énfasis en el estudio de las interacciones de los neuroreceptores con los lípidos de su entorno en la membrana, y en particular con el colesterol.

Publicaciones recientes.

  • Eggeling, C., Willig, K.I. & Barrantes, F. (2013). STED microscopy of living cells – New frontiers in Membrane and Neurobiology. J. Neurochemistry 126: 203-212.
  • Willig, K.I. & Barrantes, F.J. (2014). Recent Applications of Superresolution Microscopy in Neurobiology. Current Opin. Chem. Biol. 20:16-21.
  • Vallés, A.S., Borroni, M.V. and Barrantes, F.J. (2014). Targeting α7 type brain nicotinic acetylcholine receptors in Alzheimer’s disease: Rationale and current status. CNS Drugs 28:975–987.
  • Barrantes F.J. (2014). Cell-surface translational dynamics of nicotinic acetylcholine receptors. Front. Synaptic Neurosci. 6:25, 1-16.
  • Barrantes, F.J. (2015). Phylogenetic conservation of protein-lipid motifs in pentameric ligand-gated ion channels. Biochim. Biophys. Acta. Biomembr. 1848: 1796–1805.
  • Pissinis, D.E., Díaz, C., Maza, E., Bonini, I.C., Barrantes, F.J., Salvarezza, R.C. and Schilardi, P.L. (2015). Functional nicotinic acetylcholine receptor reconstitution in Au(111)-supported thiolipid monolayers. Nanoscale 7: 15789-157
  • Mulcahy, M.J., Blattman, S.B., Barrantes, F.J., Lukas, R.J. and Hawrot, E. (2015). Resistance to inhibitors of cholinesterase 3 (Ric-3) expression promotes selective protein associations with the human α7-nicotinic acetylcholine receptor interactome. PLoS One. 10(8):e0134409.
  • Perez-Lloret, S. & Barrantes, F.J. (2016). Deficits in cholinergic neurotransmission and their clinical correlates in Parkinson’s disease. Nature Parkinson´s Disease 2, 16001.
  • Barrantes, F.J. (2016). Gregorio Weber’s roots in Argentina. Springer Series on Fluorescence: Perspectives on Fluorescence: Weber, G. ed. by David M. Jameson. Springer. Chapter 2, pp 1-24. doi: 10.1007/4243_2016_9
  • Barrantes, F.J. & Fantini, J. (2016). From hopanoids to cholesterol: molecular clocks of pentameric ligand-gated ion channels. Prog Lipid Res. 63:1-13. Almarza, G., Sánchez, F. and Barrantes, F.J. (2014). Transient cholesterol effects on nicotinic acetylcholine receptor surface mobility. PloS One 9:e100346.
  • Fantini, J., Di Scala, C., Evans, L.S., Williamson, P.T.S. & Barrantes, F.J. (2016). A mirror code for protein-cholesterol interactions in the two leaflets of biological membranes. Sci. Reports 6:21907.
The Nature, Origin and Propagation of the Electric Field: A New Insight to Fundamental Physics

The Nature, Origin and Propagation of the Electric Field: A New Insight to Fundamental Physics

joshiJoshi Anturkar, Narahari Department of Physics, University of Los Andes, Merida, Venezuela Email: joshi@ula.ve

Se presentan puntos de vista no convencionales para las teorías establecidas y utilizadas durante dos siglos. El tema es de interés general y de gran significado. El campo del electromagnetismo forma parte fundamental de la ciencia y la tecnología y he presentado algunas novedades sobre la naturaleza del campo eléctrico y su propagación, con el propósito de entender por que la carga del electrón es eterna.

The Nature, Origin and Propagation of the Electric Field: A New Insight to Fundamental Physics
Narahari V. Joshi
PDF (413 K)  Pub. Date: June 21, 2016

Abstract. The nature, origin and propagation of the electric field are discussed for the first time on the basis of the presence of vibrating strings in the space and their self-excitation process. It is considered that the electron is formed from strings and it has specific vibrational frequency. This excites the strings which are close by with the self-excitation process. This procedure continuous in the space according to the symmetry and vibrational energy in the form of waves spread near the electron (or the charge particle) which behaves and carries energy known as electric field. In fact, the electron does not continuously emit energy in any form but induces (or excites) and organizes energy in a self-sustain vibrational form and extends in three dimensional space. Only on the basis of the presence of strings (vibrational energy), several electromagnetic phenomena have been explained in a consistent way. The vibrational nature of the electric field is also examined with the help of Stark effect and X-ray diffraction approach to support the present view.

Confirma la existencia de elementos (vibrating strings)en el espacio que absorben la energía eléctrica; sus implicaciones.

Gauss’s Law: Re-Examination and Its Consequences

Narahari V. Joshi Faculty of Science, University of Los Andes, Merida, Venezuela
PDF (312 K) HTML XML Pub. Date: November 17, 2015

Abstract. Gauss’s law is modified to take into account the absorption of the electric field by vacuum. It has important consequences as the absorbed energy becomes a part of the vacuum energy and excites the energy of strings in a form of quantum harmonic oscillators. Thus, vacuum becomes an excitable medium and this helps to understand the basic mechanisms for the conservation of the charge