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      Cryo-EM of retinoschisin branched networks suggests an intercellular adhesive scaffold in the retina


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          Mutations in the essential retinal protein retinoschisin (RS1) cause a form of macular degeneration. Heymann et al. use cryo-EM to show that RS1 assembles into branched networks that may play a stabilizing role in maintaining the integrity of the retina.


          Mutations in the retinal protein retinoschisin (RS1) cause progressive loss of vision in young males, a form of macular degeneration called X-linked retinoschisis (XLRS). We previously solved the structure of RS1, a 16-mer composed of paired back-to-back octameric rings. Here, we show by cryo–electron microscopy that RS1 16-mers can assemble into extensive branched networks. We classified the different configurations, finding four types of interaction between the RS1 molecules. The predominant configuration is a linear strand with a wavy appearance. Three less frequent types constitute the branch points of the network. In all cases, the “spikes” around the periphery of the double rings are involved in these interactions. In the linear strand, a loop (usually referred to as spike 1) occurs on both sides of the interface between neighboring molecules. Mutations in this loop suppress secretion, indicating the possibility of intracellular higher-order assembly. These observations suggest that branched networks of RS1 may play a stabilizing role in maintaining the integrity of the retina.

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          Most cited references 49

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          Characteristics of a Human Cell Line Transformed by DNA from Human Adenovirus Type 5

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            The distribution and function of phosphatidylserine in cellular membranes.

            Phosphatidylserine (PS) is the most abundant negatively charged phospholipid in eukaryotic membranes. PS directs the binding of proteins that bear C2 or gamma-carboxyglutamic domains and contributes to the electrostatic association of polycationic ligands with cellular membranes. Rather than being evenly distributed, PS is found preferentially in the inner leaflet of the plasma membrane and in endocytic membranes. The loss of PS asymmetry is an early indicator of apoptosis and serves as a signal to initiate blood clotting. This review discusses the determinants and functional implications of the subcellular distribution and membrane topology of PS.
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              Transmembrane proteins of the tight junctions at the blood-brain barrier: structural and functional aspects.

              The blood-brain barrier (BBB) is formed by microvascular endothelial cells sealed by tetraspanning tight junction (TJ) proteins, such as claudins and TAMPs (TJ-associated marvel proteins, occludin and tricellulin). Claudins are the major components of the TJs. At the BBB, claudin-5 dominates the TJs by preventing the paracellular permeation of small molecules. On the other hand, TAMPs regulate the structure and function of the TJs; tricellulin may tighten the barrier for large molecules. This review aims at integrating and summarizing the most relevant and recent work on how the BBB is influenced by claudin-1, -3, -5, -12 and the TAMPs occludin and tricellulin, all of which are four-transmembrane TJ proteins. The exact functions of claudin-1, -3, -12 and TAMPs at this barrier still need to be elucidated.

                Author and article information

                J Cell Biol
                J. Cell Biol
                The Journal of Cell Biology
                Rockefeller University Press
                04 March 2019
                : 218
                : 3
                : 1027-1038
                [1 ]Laboratory for Structural Biology Research, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD
                [2 ]Section on Translational Research for Retinal and Macular Degeneration, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD
                [3 ]Cryo-Electron Microscopy Facility, Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA
                [4 ]National Eye Institute, National Institutes of Health, Bethesda, MD
                Author notes
                Correspondence to J. Bernard Heymann: heymannb@ 123456mail.nih.gov
                © 2019 Heymann et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

                Funded by: National Institutes of Health, DOI https://doi.org/10.13039/100000002,%22National%20Institutes%20of%20Health%22,;
                Funded by: National Eye Institute, DOI https://doi.org/10.13039/100000053,%22National%20Eye%20Institute%22,;
                Funded by: National Institute on Deafness and Other Communication Disorders, DOI https://doi.org/10.13039/100000055,%22National%20Institute%20on%20Deafness%20and%20Other%20Communication%20Disorders%22,;
                Funded by: National Institute for Arthritis, Musculoskeletal and Skin Diseases
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                Cell biology


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