TY  - INPR
A1  - Birtasu, Alexandra N.
A1  - Wieland, Konstantin
A1  - Ermel, Utz Heinrich
A1  - Rahm, Johanna V.
A1  - Scheffer, Margot
A1  - Flottmann, Benjamin
A1  - Heilemann, Mike
A1  - Grahammer, Florian
A1  - Frangakis, Achilleas S.
T1  - The molecular architecture of the kidney slit diaphragm
T2  - bioRxiv
N2  - Vertebrate life depends on renal function to filter excess fluid and remove low-molecular-weight waste products. An essential component of the kidney filtration barrier is the slit diaphragm (SD), a specialized cell-cell junction between podocytes. Although the constituents of the SD are largely known, its molecular organization remains elusive. Here, we use super-resolution correlative light and electron microscopy to quantify a linear rate of reduction in albumin concentration across the filtration barrier. Next, we use cryo-electron tomography of vitreous lamellae from high-pressure frozen native glomeruli to analyze the molecular architecture of the SD. The resulting densities resemble a fishnet pattern. Fitting of Nephrin and Neph1, the main constituents of the SD, results in a complex interaction pattern with multiple contact sites between the molecules. Using molecular dynamics flexible fitting, we construct a blueprint of the SD, where we describe all interactions. Our architectural understanding of the SD reconciles previous findings and provides a mechanistic framework for the development of novel therapies to treat kidney dysfunction.
Y1  - 2023
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/79471
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-794714
UR  - https://www.biorxiv.org/content/10.1101/2023.10.27.564405v3
IS  - 2023.10.27.564405, Version 3
ER  -