| Structural highlights
Function
SID1_CAEEL Plays a role in RNA-mediated gene silencing by acting cell-autonomously as a channel for the transport of double-stranded RNA (dsRNA) between cells. Mediates the spread of dsRNA and subsequent silencing of genes in cells distant from the site of dsRNA introduction. Selective for dsRNA. Preferentially binds long dsRNA, from 50 base pairs up to 700. Short 20 base-pair long molecules are not bound. May also bind dsDNA, but with lower affinity. Binding may be sequence-independent (PubMed:26067272). Required for avoidance behavior induced by small RNAs derived from pathogenic bacteria such as P.aeruginosa (PubMed:32908307).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
Publication Abstract from PubMed
The nucleic acid transport properties of the systemic RNAi-defective (SID) 1 family make them attractive targets for developing RNA-based therapeutics and drugs. However, the molecular basis for double-stranded (ds) RNA recognition by SID1 family remains elusive. Here, we report the cryo-EM structures of Caenorhabditis elegans (c) SID1 alone and in complex with dsRNA, both at a resolution of 2.2 A. The dimeric cSID1 interacts with two dsRNA molecules simultaneously. The dsRNA is located at the interface between beta-strand rich domain (BRD)1 and BRD2 and nearly parallel to the membrane plane. In addition to extensive ionic interactions between basic residues and phosphate backbone, several hydrogen bonds are formed between 2'-hydroxyl group of dsRNA and the contact residues. Additionally, the electrostatic potential surface shows three basic regions are fitted perfectly into three major grooves of dsRNA. These structural characteristics enable cSID1 to bind dsRNA in a sequence-independent manner and to distinguish between DNA and RNA. The cSID1 exhibits no conformational changes upon binding dsRNA, with the exception of a few binding surfaces. Structural mapping of dozens of loss-of-function mutations allows potential interpretation of their diverse functional mechanisms. Our study marks an important step toward mechanistic understanding of the SID1 family-mediated dsRNA uptake.
Structural basis for double-stranded RNA recognition by SID1.,Wang R, Cong Y, Qian D, Yan C, Gong D Nucleic Acids Res. 2024 May 14:gkae395. doi: 10.1093/nar/gkae395. PMID:38742627[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Winston WM, Molodowitch C, Hunter CP. Systemic RNAi in C. elegans requires the putative transmembrane protein SID-1. Science. 2002 Mar 29;295(5564):2456-9. PMID:11834782 doi:10.1126/science.1068836
- ↑ Feinberg EH, Hunter CP. Transport of dsRNA into cells by the transmembrane protein SID-1. Science. 2003 Sep 12;301(5639):1545-7. PMID:12970568 doi:10.1126/science.1087117
- ↑ Tijsterman M, May RC, Simmer F, Okihara KL, Plasterk RH. Genes required for systemic RNA interference in Caenorhabditis elegans. Curr Biol. 2004 Jan 20;14(2):111-6. PMID:14738731 doi:10.1016/j.cub.2003.12.029
- ↑ Hunter CP, Winston WM, Molodowitch C, Feinberg EH, Shih J, Sutherlin M, Wright AJ, Fitzgerald MC. Systemic RNAi in Caenorhabditis elegans. Cold Spring Harb Symp Quant Biol. 2006;71:95-100. PMID:17381285 doi:10.1101/sqb.2006.71.060
- ↑ Shih JD, Fitzgerald MC, Sutherlin M, Hunter CP. The SID-1 double-stranded RNA transporter is not selective for dsRNA length. RNA. 2009 Mar;15(3):384-90. PMID:19155320 doi:10.1261/rna.1286409
- ↑ Jose AM, Smith JJ, Hunter CP. Export of RNA silencing from C. elegans tissues does not require the RNA channel SID-1. Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2283-8. PMID:19168628 doi:10.1073/pnas.0809760106
- ↑ Calixto A, Chelur D, Topalidou I, Chen X, Chalfie M. Enhanced neuronal RNAi in C. elegans using SID-1. Nat Methods. 2010 Jul;7(7):554-9. PMID:20512143 doi:10.1038/nmeth.1463
- ↑ Shih JD, Hunter CP. SID-1 is a dsRNA-selective dsRNA-gated channel. RNA. 2011 Jun;17(6):1057-65. PMID:21474576 doi:10.1261/rna.2596511
- ↑ Kobayashi I, Tsukioka H, Kômoto N, Uchino K, Sezutsu H, Tamura T, Kusakabe T, Tomita S. SID-1 protein of Caenorhabditis elegans mediates uptake of dsRNA into Bombyx cells. Insect Biochem Mol Biol. 2012 Feb;42(2):148-54. PMID:22178129 doi:10.1016/j.ibmb.2011.11.007
- ↑ Mon H, Kobayashi I, Ohkubo S, Tomita S, Lee J, Sezutsu H, Tamura T, Kusakabe T. Effective RNA interference in cultured silkworm cells mediated by overexpression of Caenorhabditis elegans SID-1. RNA Biol. 2012 Jan;9(1):40-6. PMID:22293577 doi:10.4161/rna.9.1.18084
- ↑ McEwan DL, Weisman AS, Hunter CP. Uptake of extracellular double-stranded RNA by SID-2. Mol Cell. 2012 Sep 14;47(5):746-54. PMID:22902558 doi:10.1016/j.molcel.2012.07.014
- ↑ Li W, Koutmou KS, Leahy DJ, Li M. Systemic RNA Interference Deficiency-1 (SID-1) Extracellular Domain Selectively Binds Long Double-stranded RNA and Is Required for RNA Transport by SID-1. J Biol Chem. 2015 Jul 31;290(31):18904-13. PMID:26067272 doi:10.1074/jbc.M115.658864
- ↑ Kaletsky R, Moore RS, Vrla GD, Parsons LR, Gitai Z, Murphy CT. C. elegans interprets bacterial non-coding RNAs to learn pathogenic avoidance. Nature. 2020 Oct;586(7829):445-451. PMID:32908307 doi:10.1038/s41586-020-2699-5
- ↑ Wang R, Cong Y, Qian D, Yan C, Gong D. Structural basis for double-stranded RNA recognition by SID1. Nucleic Acids Res. 2024 May 14:gkae395. PMID:38742627 doi:10.1093/nar/gkae395
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