The kidney slit diaphragm resembles a fishnet
Alexandra N. Birtasu, Konstantin Wieland, Utz H. Ermel, Serena M. Arghittu, Sina Manger, Maciej K. Kocylowski, Bernd Fakler, Margot P. Scheffer, Roberto Covino, Florian Grahammer, Achilleas S. Frangakis
Abstract
INTRODUCTION: An essential component of the kidney filtration barrier, the slit diaphragm, is a specialized cell-cell junction composed of the cell adhesion molecules Nephrin and Neph1. METHODS: Here, we use cryo-electron tomography of vitreous lamellae from high pressure frozen wild-type C57BL/6J native mouse glomeruli. RESULTS: The cryo-electron tomograms show that the slit diaphragm resembles a fishnet-like architecture. After sub-tomogram averaging and molecular dynamics flexible fitting of Nephrin and Neph1, the resulting molecular model of the slit diaphragm reveals a criss-cross arrangement of these cell adhesion molecules with multiple homo- and hetero-philic interactions. This renders the slit diaphragm as a single- or a multi-layer fishnet, quasi-crystalline, sheet-like molecular polymer that can provide both stability and flexibility to compensate for mechanical forces. CONCLUSIONS: The molecular architecture of the murine slit diaphragm provides a mechanistic framework for comprehending kidney cell-cell junctions with immediate implications in disease.