Scientific Seminars

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The voltage-gated sodium (Nav) channels are responsible for the initiation and propagation of action potentials. Being associated with a variety of channelopathies, they are targeted by multiple pharmaceutical drugs and natural toxins. We determined the crystal structure of a bacterial Nav channel NavRh in a potentially inactivated state a few years ago, which is a homotetramer in primary sequence but exhibits structural asymmetry. Employing the modern methods of cryo-EM, we determined the near atomic resolution structures of a Nav channel from American cockroach (designated NavPaS) and from electric eel (designated EeNav1.4). Most recently, we have determined the cryo-EM structures of the human Nav channels, Nav1.2, Nav1.4, and Nav1.7 in complex with distinct auxiliary subunits and toxins.These structures reveal the folding principle and structural details of the single-chain eukaryotic Nav channels that are distinct from homotetrameric voltage-gated ion channels. Unexpectedly, the two structures were captured in drastically different states. Whereas the structure of NavPaS has a closed pore and the four VSDs in distinct conformations, that of EeNav1.4 and the human channels is open at the intracelluar gate with VSDs exhibiting similar “up”states. The most striking conformational differenc occurs to the III-IV linker, which is essential for fast inactivation. Based on the structural features, we suggest an allosteric blocking mechanism for fast inactivation of Nav channels by the IFM motif. Structural comparison of the conformationally distinct Nav channels provides important insights into the electromechanical coupling mechanism of Nav channels and offers the 3D template to map hundreds of disease mutations.

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We have pioneered a new model organism for aging research, the naturally short-lived African killifish Nothobranchius furzeri. The African killifish lives in ephemeral pools of water in Africa, and has evolved a short life cycle adapted to this habitat. Its embryos can also resist drought until the next wet season in a state of ‘suspended life’. In laboratory conditions, the African killifish has a maximal lifespan of about 4-6 months, and is, so far, the shortest-lived vertebrate that can be bred in captivity. The natural short lifespan make the African killifish an ideal model to probe the mechanisms of aging in vertebrates. We have successfully transformed this natural short-lived vertebrate into a usable model organism for aging research. We have completed the first de novo assembly of the African killifish genome using deep sequencing and have successfully developed CRISPR-Cas9 mediated genome-editing in this fish. The development of modern genomic tools in the African killifish are major steps in pioneering this species as a new vertebrate model for aging research. Our goal is to use this model to discover new principles underlying aging, longevity, and ‘suspended animation’ in vertebrates. We already identified several loci associated with survival between different strains of the African killifish from different regions. Using genome-editing, we have generated strains deficient for several genes in nutrient-sensing and epigenetic pathways. We want to develop this system to examine the role of new vertebrate-specific genes in aging. We are excited to use this system to understand the principles underlying ‘suspended animation’ and whether they have the ability to preserve tissues and organs long-term.

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The sun is the source of most living things on earth, and living organisms use light energy as a source of energy to drive their physiological activities and as a source of information to perceive the surrounding environment, which is useful for their own survival. The two most familiar strategies for the use of light are the vision of animals, including humans, and the photosynthesis of plants.

In photosynthesis, complexes of chlorophyll pigments and large proteins, called the photosystem exists in chloroplasts and other parts of plants, absorb the energy of sunlight and undergoes a highly efficient charge-separation reaction to produce the chemical energy necessary for the synthesis of adenosine triphosphate (ATP) and carbohydrates. On the other hand, in animal vision, the shape and color of objects seen by the eye are recognized by rhodopsin, a photoreceptor membrane protein located in the retina, which captures light entering through a lens in eye and transmits this information to the brain through the optic nerve.

In recent years, it was revealed that many microbes such as bacteria and unicellular eukaryotic microbes, has their own photoreceptive proteins called microbial rhodopsin, similar to animal rhodopsin. Both of these are membrane proteins consisting of seven ɑ-helices, with a retinal pigment, a derivative of vitamin A, bound to the protein to absorb visible light. However, unlike animal rhodopsin, microbial rhodopsin uses the light energy to transport various ions, such as protons, sodium and chloride ions, into and out of the cells, and to control gene expression with light, to regulate enzymatic activity in a light-dependent manner, etc.

In recent years, these microbial rhodopsins have been used as a major molecular tool in "optogenetics," a new methodology to manipulate the neural activity in animals by light. In this webinar, I will present the photobiology of microbial rhodopsins, the chemical and molecular mechanisms, as well as the applications in optogenetics.