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PLoS One
2021 Jul 21;167:e0254917. doi: 10.1371/journal.pone.0254917.
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Evolutionary conservation of intrinsically unstructured regions in slit-diaphragm proteins.
Mulukala SKN
,
Kambhampati V
,
Qadri AH
,
Pasupulati AK
.
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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.
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Fig 1. Distribution of SD proteins and their orthologs in vertebrates and invertebrates.A) Nephrin, B) KIRREL1, C) CD2AP, D) Podocin, and E) TRPC6. Only organisms with complete genome sequences were considered for the study. Note: Blue thick lines represent the vertebrate phyla.
Fig 2. Domain organization in nephrin and its orthologs.Different colors represent Ig domain subsets: Ig3 as green, CD80-like C2-set as red, IgV as blue, FN-3 as light blue, and intrinsically disordered regions as yellow bubbles.
Fig 3. Domain organization in KIRREL1 and its orthologs.Different colors represent the Ig domain subsets: Ig2 as pink, Ig3 as green, I-set as light blue, CD80-like C2-set as red, Ig V-set as dark blue, and intrinsically disordered regions as yellow bubbles.
Fig 4. Domain organization in CD2AP and CINDR sequences.Note: Yellow bubbles represent the intrinsically disordered regions.
Fig 5. Domain organization of podocin sequences of the chordate phylum.Note: Yellow bubbles represent the intrinsically disordered regions.
Fig 6. Domain organization in TRPC6, TRPC3, and TRPC7 sequences.The ankyrin repeats in the sequences are represented as a pink rectangle; similarly, the yellow rectangle represents TRP domains, and teal represents the ion transport domain, and the yellow bubbles represent the intrinsically disordered regions.
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