Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India.
PLoS One. 2021 Jul 21;16(7):e0254917. doi: 10.1371/journal.pone.0254917. eCollection 2021.
Vertebrate kidneys contribute to homeostasis by regulating electrolyte, acid-base balance, removing toxic metabolites from blood, and preventing protein loss into the urine. Glomerular podocytes constitute the blood-urine barrier, and podocyte slit-diaphragm (SD), a modified tight junction, contributes to the glomerular permselectivity. Nephrin, KIRREL1, podocin, CD2AP, and TRPC6 are crucial members of the SD that interact with each other and contribute to the SD's structural and functional integrity. This study analyzed the distribution of these five essential SD proteins across the organisms for which the genome sequence is available. We found a diverse distribution of nephrin and KIRREL1 ranging from nematodes to higher vertebrates, whereas podocin, CD2AP, and TRPC6 are restricted to the vertebrates. Among invertebrates, nephrin and its orthologs consist of more immunoglobulin-3 domains, whereas in the vertebrates, CD80-like C2-set domains are predominant. In the case of KIRREL1 and its orthologs, more Ig domains were observed in invertebrates than vertebrates. Src Homology-3 (SH3) domain of CD2AP and SPFH domain of podocin are highly conserved among vertebrates. TRPC6 and its orthologs had conserved ankyrin repeats, TRP, and ion transport domains, except Chondrichthyes and Echinodermata, which do not possess the ankyrin repeats. Intrinsically unstructured regions (IURs) are conserved across the SD orthologs, suggesting IURs importance in the protein complexes that constitute the slit-diaphragm. For the first time, a study reports the evolutionary insights of vertebrate SD proteins and their invertebrate orthologs.
脊椎动物的肾脏通过调节电解质和酸碱平衡、从血液中清除有毒代谢物以及防止蛋白质丢失到尿液中来维持体内平衡。肾小球足细胞构成了血液-尿液屏障，而足细胞裂孔隔膜（SD）是一种改良的紧密连接，有助于肾小球的选择性通透。nephrin、KIRREL1、podocin、CD2AP 和 TRPC6 是 SD 的重要成员，它们相互作用，有助于 SD 的结构和功能完整性。本研究分析了这些五个必不可少的 SD 蛋白在基因组序列可用的生物体中的分布。我们发现，nephrin 和 KIRREL1 的分布多种多样，从线虫到高等脊椎动物都有，而 podocin、CD2AP 和 TRPC6 则仅限于脊椎动物。在无脊椎动物中，nephrin 及其同源物包含更多的免疫球蛋白 3 结构域，而在脊椎动物中，CD80 样 C2 集结构域则占主导地位。在 KIRREL1 和其同源物的情况下，无脊椎动物中观察到更多的 Ig 结构域。CD2AP 的 Src Homology-3 (SH3) 结构域和 podocin 的 SPFH 结构域在脊椎动物中高度保守。TRPC6 和其同源物具有保守的锚蛋白重复、TRP 和离子转运结构域，但软骨鱼纲和棘皮动物纲除外，它们不具有锚蛋白重复。SD 同源物中的无规则卷曲区域（IUR）是保守的，这表明 IUR 在构成裂孔隔膜的蛋白质复合物中的重要性。这是首次报道脊椎动物 SD 蛋白及其无脊椎动物同源物的进化见解。
