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Review
. 2017 Feb;14(2):164-170.
doi: 10.1080/15476286.2016.1267097. Epub 2016 Dec 12.

Effects of Aicardi-Goutières syndrome mutations predicted from ADAR-RNA structures

Andrew J Fisher  1   2 , Peter A Beal  1
Affiliations
Review

Effects of Aicardi-Goutières syndrome mutations predicted from ADAR-RNA structures

Andrew J Fisher et al. RNA Biol. 2017 Feb.

Abstract

Adenosine (A) to inosine (I) RNA editing is important for life in metazoan organisms. Dysregulation or mutations that compromise the efficacy of A to I editing results in neurological disorders and a shorten life span. These reactions are catalyzed by adenosine deaminases acting on RNA (ADARs), which hydrolytically deaminate adenosines in regions of duplex RNA. Because inosine mimics guanosine in hydrogen bonding, this prolific RNA editing alters the sequence and structural information in the RNA landscape. Aicardi-Goutières syndrome (AGS) is a severe childhood autoimmune disease that is one of a broader set of inherited disorders characterized by constitutive upregulation of type I interferon (IFN) referred to as type I interferonopathies. AGS is caused by mutations in multiple genes whose protein products, including ADAR1, are all involved in nucleic acid metabolism or sensing. The recent crystal structures of human ADAR2 deaminase domain complexed with duplex RNA substrates enabled modeling of how AGS causing mutations may influence RNA binding and catalysis. The mutations can be broadly characterized into three groups; mutations on RNA-binding loops that directly affect RNA binding, "second-layer" mutations that can alter the disposition of RNA-binding loops, and mutations that can alter the position of an α-helix bearing an essential catalytic residue.

Keywords: ADAR; Aicardi-Goutieres Syndrome; base-flipping; A to I; inosine; RNA editing.

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Figures

Figure 1.
Figure 1.
Primary structure of ADAR. (A) Schematic representation of the modular domains of the three human ADARs. Catalytic deaminase domain is represented in yellow. (B) Sequence alignment of ADAR deaminase domains from diverse organisms. The secondary structural elements observed in the human ADAR2 X-ray structure are represented above the sequence alignment. The seven AGS-causing missense mutations are marked with cyan-colored triangles below the sequence. The catalytic Glutamate is marked by a magenta square, and the ADAR-specific RNA-binding loop is highlighted by a green line.
Figure 2.
Figure 2.
Overall ribbon view of hADAR2d complexed with dsRNA substrate. The protein is colored in the rainbow spectrum starting with blue at the N-terminus and ending with red at the C-terminus. The secondary structure elements are labeled. RNA is colored in sand with the 8-azaN flipped out interacting with the Zn2+ ion, gray colored sphere. IHP, which is mostly obscured in this view, is drawn as sticks. Numbers in red indicate equivalent hADAR1 numbering.
Figure 3.
Figure 3.
hADAR1 AGS-causing mutants mapped onto the hADAR2-dsRNA complex structure. (A) The hADAR2 structure drawn as white-colored tube, with the ADAR-specific RNA-binding loop colored in darker gray, which was disordered in the hADAR2d RNA-free structure. The hADAR2 residues equivalent to the hADAR1 AGS-causing mutations are show in cyan with black labels. hADAR1 AGS-causing mutations are labeled in red text, mapped onto the structure. Glu488, which pushed out the edited base is drawn in green sticks, Zn2+ ion in yellow sphere, and IHP is dawn in sticks with magenta-colored carbons. (B) Space-filling representation rotated slightly with respect to (a).
Figure 4.
Figure 4.
Close-up view of active site revealing the location of the two buried ADAR1 AGS-causing mutations A870T and I872T (cyan) mapped on the hADAR2 structure. Invariant catalytic residue Glu396/E912 hydrogen-bonds (orange dashed lines) with flipped-out edited base analog; 8-azaN. Zinc coordination is illustrated with yellow dashed lines, and conserved Arginines of helix α2 that interact with IHP phosphates are shown with magenta dashed lines.
Figure 5.
Figure 5.
“Second-layer” AGS mutations of hADAR1 Y1112F and D1113H (cyan) mapped on hADAR2 structure. Ala587, equivalent to ADAR1 Y1112F, points toward Glu461, C976 in ADAR1, which is part of the ADAR-specific RNA-binding loop (shown with gray-colored main chain tube). hADAR1 and hADAR2 numbering are in red and black, respectively.
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References

    1. Grosjean H. Fine-tuning of RNA functions by modification and editing. Berlin; New York: Springer, 2005.
    1. Zipeto MA, Jiang Q, Melese E, Jamieson CH. RNA rewriting, recoding, and rewiring in human disease. Trends Mol Med 2015; 21:549-59; PMID:26259769; http://dx.doi.org/10.1016/j.molmed.2015.07.001 - DOI - PubMed
    1. Bass BL, Weintraub H. An unwinding activity that covalently modifies its double-stranded RNA substrate. Cell 1988; 55:1089-98; PMID:3203381; http://dx.doi.org/10.1016/0092-8674(88)90253-X - DOI - PubMed
    1. Macbeth MR, Schubert HL, Vandemark AP, Lingam AT, Hill CP, Bass BL. Inositol hexakisphosphate is bound in the ADAR2 core and required for RNA editing. Science 2005; 309:1534-9; PMID:16141067; http://dx.doi.org/10.1126/science.1113150 - DOI - PMC - PubMed
    1. Picardi E, Manzari C, Mastropasqua F, Aiello I, D'Erchia AM, Pesole G. Profiling RNA editing in human tissues: towards the inosinome Atlas. Sci Rep 2015; 5:14941; PMID:26449202; http://dx.doi.org/10.1038/srep14941 - DOI - PMC - PubMed

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