Modomics - A Database of RNA Modifications

ID Card:

Full name: Double-stranded RNA-specific editase 1
Synonym: ADAR2,DRADA2, RED1
GI: 2829669
UniProt: P78563
Structures: | 1ZY7 | 5ED1 | 5ED2 | 5HP2 | 5HP3 | 6D06 | 6VFF | 7KFN |
Alpha Fold Predicted Structure: AF-P78563-F1
Enzyme type: deaminase


PDB Structures:


1ZY7

Structure Description:

Title:
Classification:
Technique:

Abstract of the PDB Structure's related Publication:

We report the crystal structure of the catalytic domain of human ADAR2, an RNA editing enzyme, at 1.7 angstrom resolution. The structure reveals a zinc ion in the active site and suggests how the substrate adenosine is recognized. Unexpectedly, inositol hexakisphosphate (IP6) is buried within the enzyme core, contributing to the protein fold. Although there are no reports that adenosine deaminases that act on RNA (ADARs) require a cofactor, we show that IP6 is required for activity. Amino acids that coordinate IP6 in the crystal structure are conserved in some adenosine deaminases that act on transfer RNA (tRNA) (ADATs), related enzymes that edit tRNA. Indeed, IP6 is also essential for in vivo and in vitro deamination of adenosine 37 of tRNAala by ADAT1.

Download RCSB-PDB Structures:

Pdb Files   1ZY7.pdb   5ED1.pdb   5ED2.pdb   5HP2.pdb   5HP3.pdb   6D06.pdb   6VFF.pdb   7KFN.pdb  
Pdbx/mmCIF Files   1ZY7.cif   5ED1.cif   5ED2.cif   5HP2.cif   5HP3.cif   6D06.cif   6VFF.cif   7KFN.cif  


Protein sequence:

MDIEDEENMSSSSTDVKENRNLDNVSPKDGSTPGPGEGSQLSNGGGGGPGRKRPLEEGSNGHSKYRLKKRRKTPGPVLPKNALMQLNEIKPGLQYTLLSQTGPVHAPLFVMSVEVNGQVFEGSGPTKKKAKLHAAEKALRSFVQFPNASEAHLAMGRTLSVNTDFTSDQADFPDTLFNGFETPDKAEPPFYVGSNGDDSFSSSGDLSLSASPVPASLAQPPLPVLPPFPPPSGKNPVMILNELRPGLKYDFLSESGESHAKSFVMSVVVDGQFFEGSGRNKKLAKARAAQSALAAIFNLHLDQTPSRQPIPSEGLQLHLPQVLADAVSRLVLGKFGDLTDNFSSPHARRKVLAGVVMTTGTDVKDAKVISVSTGTKCINGEYMSDRGLALNDCHAEIISRRSLLRFLYTQLELYLNNKDDQKRSIFQKSERGGFRLKENVQFHLYISTSPCGDARIFSPHEPILEGSRSYTQAGVQWCNHGSLQPRPPGLLSDPSTSTFQGAGTTEPADRHPNRKARGQLRTKIESGEGTIPVRSNASIQTWDGVLQGERLLTMSCSDKIARWNVVGIQGSLLSIFVEPIYFSSIILGSLYHGDHLSRAMYQRISNIEDLPPLYTLNKPLLSGISNAEARQPGKAPNFSVNWTVGDSAIEVINATTGKDELGRASRLCKHALYCRWMRVHGKVPSHLLRSKITKPNVYHESKLAAKEYQAAKARLFTAFIKAGLGAWVEKPTEQDQFSLTP

Comments:

Double-stranded RNA-specific adenosine deaminase enzymes (DSRAD) belong to the Adenosine deaminase acting on RNA (ADAR) gene family. Being an highly conserved group of enzymes they share a conserved domain architecture consisting of a variable number of N-terminal dsRNA binding domains (dsRBDs) and a C-terminal catalytic deaminase domain (Savva et al. 2012 ). ADAR is responsible for three modification along BLCAP mRNA that change the encoded protein, downstream of translation (Savva et al. 2012 ). These modifications bring to 8 possible BLCAP isoforms, with an amino acid switch from Y to C, Q to R, and K to R. ADARB1 modifies 5b and 5c positions in the BLCAP of 3'UTR. The distribution of serotonin (5HT)2C receptor (5HT2CR) in the brain suggests specific roles in normal physiology and in disease development such as in the case of, obesity, anxiety, epilepsy, sleep disorders, and motor dysfunction when dysregulated. 5HT2CR's mRNA secondary structure differences between human, mouse, and rat transcripts suggest that ADAR does not have an intrinsic ability to recognize consensus sequences within its substrates. ADAR and ADARB1 edit AUA, AAU, and AUU codons in 5HT2CR that translate for Isoleucine 156 (I156), Asparagine 158 (N158), and I 160 (I160), along the translated protein. Editing sites in 5HT2CR are A, B, C, C', and D, placed in the first and third, first and second, and first coding positions of the three editing codons, respectively. A, B, C, C', and D are in the 466, 468, 472, 473, and 478 nucleotide positions, respectively. Thirtytwo editing-derived permutations are virtually possible. Nevertheless, only two editing profiles have been experimentally observed, among which is the unedited profile. In the partially edited profile, A and D sites are edited by ADAR and ADARB1, respectively. In the fully edited profile also B, C, and C' sites are edited by both of the two active ADAR isoforms. It appears that a cross-talk between ADAR isoforms exists and influences the modification profile of the intra-exonic region of the 5HT2CR, determined by the relative expression of ADAR and ADARB1. Therefore, an interplay between the two enzymes on the shared editing sites is tempting to be inferred. (Werry et al. 2008 ) α3 subunit of the GABAA receptor is an editing substrate for either ADAR and ADARB1. Editing of the third codon position of AUA codon triggers the I:M amino acid change, in the translated protein. Given the increasing editing extent that starts at birth and becomes close to 100% in the adult brain, it has been suggested that editing of Gabra-3 mRNA is important for normal brain development.( Ohlson et al. 2007)




Reaction Substrate SubstrateType Position (Anti)Codon Modified (Anti)Codon Amino Acid Change Transcript Name Transcript Region Cellular Localization References
A:I RNA pre-mRNA 5b BLCAP 3'UTR Nucleus 19908260   
A:I RNA pre-mRNA 5c BLCAP 3'UTR Nucleus 19908260   
A:I RNA pre-mRNA 4 TAT TIT Y:C BLCAP protein-coding region Nucleus 19908260   
A:I RNA pre-mRNA 14 CAG CIG Q:R BLCAP protein-coding region Nucleus 19908260   
A:I RNA pre-mRNA 44 AAG AIG K:R BLCAP protein-coding region Nucleus 19908260   
A:I RNA pre-mRNA 478 AUU IUU I:V HTR2C protein-coding region Nucleus 18554725   
A:I RNA pre-mRNA 472-473 AAU IIU N:G HTR2C protein-coding region Nucleus 18554725   
A:I RNA pre-mRNA 15 AUA AUI I:M GABA-3 protein-coding region Nucleus 17369310   

Alpha Fold Predicted Structure:






Clear Selection and Reset Camera

Protein sequence:

M D I E D E E N M S S S S T D V K E N R N L D N V S P K D G S T P G P G E G S Q L S N G G G G G P G R K R P L E E G S N G H S K Y R L K K R R K T P G P V L P K N A L M Q L N E I K P G L Q Y T L L S Q T G P V H A P L F V M S V E V N G Q V F E G S G P T K K K A K L H A A E K A L R S F V Q F P N A S E A H L A M G R T L S V N T D F T S D Q A D F P D T L F N G F E T P D K A E P P F Y V G S N G D D S F S S S G D L S L S A S P V P A S L A Q P P L P V L P P F P P P S G K N P V M I L N E L R P G L K Y D F L S E S G E S H A K S F V M S V V V D G Q F F E G S G R N K K L A K A R A A Q S A L A A I F N L H L D Q T P S R Q P I P S E G L Q L H L P Q V L A D A V S R L V L G K F G D L T D N F S S P H A R R K V L A G V V M T T G T D V K D A K V I S V S T G T K C I N G E Y M S D R G L A L N D C H A E I I S R R S L L R F L Y T Q L E L Y L N N K D D Q K R S I F Q K S E R G G F R L K E N V Q F H L Y I S T S P C G D A R I F S P H E P I L E G S R S Y T Q A G V Q W C N H G S L Q P R P P G L L S D P S T S T F Q G A G T T E P A D R H P N R K A R G Q L R T K I E S G E G T I P V R S N A S I Q T W D G V L Q G E R L L T M S C S D K I A R W N V V G I Q G S L L S I F V E P I Y F S S I I L G S L Y H G D H L S R A M Y Q R I S N I E D L P P L Y T L N K P L L S G I S N A E A R Q P G K A P N F S V N W T V G D S A I E V I N A T T G K D E L G R A S R L C K H A L Y C R W M R V H G K V P S H L L R S K I T K P N V Y H E S K L A A K E Y Q A A K A R L F T A F I K A G L G A W V E K P T E Q D Q F S L T P

Secondary Structure Alphabet

  • G: 3-turn helix (310helix)
  • H: α-helix
  • I: 𝝅-helix (5 - turn helix)
  • T: Hydrogen Bonded Turn
  • B: β-sheet
  • S: Bend
  • C: Coil (residues not present in any of the above conformations)
  • N: Not assigned

Download PDB Structures & DSSP Secondary Structures:

Alpha Fold Pdb Files   AF-P78563-F1.pdb  
Alpha Fold Pdbx/mmCIF Files   AF-P78563-F1.cif  
DSSP Secondary Structures   P78563.dssp  





Diseases connected to this enzyme:

Description Reaction Disease Name
A general decrease in editing activity of the human BLCAP transcript in cancerous tissues A:I
Astrocytoma
RNA editing, on different transcripts, promotes the disease risk and is closely associated with type 2 Diabetes A:I
Type 2 Diabetes
The degree of R/G editing is significantly increased in the hippocampal tissue and in neo-cortical tissue in patients A:I
Temporal Lobe Epilepsy
The reduced editing at the R/G site of glutamate receptor subunits (GluRs) is likely to reduce post-synaptic excitatory responses to glutamate, thus duce post-synaptic excitatory responses to glutamate, thus limiting the progression of cell death. A:I
Spinal Cord Injury
RNA editing in GluR-B is essential for brain development to avoid the alteration of calcium permeability which affects mice seizure and survival A:I
Severe epilepsy
RNA editing inhibits the enzymatic activity of TPH2 splice variants C:U
Psychiatric disorders
5HT2C editing is altered in individuals suffering from psychiatric disorders A:I
Psychiatric disorders
Alteration in 5HTR2C RNA editing levels in the brain of suicides A:I
Psychiatric disorders
RNA editing repairs the PINK1 W437amber mutation rescue the PINK1/Parkin-mediated mitophagy A:I
Parkinson
Hyper-editing of FLNB is closely associated with HCC pathogenesis. ADAR1 overexpression increases risk of liver cirrhosis and postoperative recurrence. ADAR1 hyper editing is associated with a poor prognosis A:I
Hepatocellular carcinoma
Hypo-editing of COPA is closely associated with HCC pathogenesis. ADAR2 downregulation increases the risk of liver cirrhosis and postoperative recurrence. It is associated withpoor prognoses A:I
Hepatocellular carcinoma
Hyperediting at the COG3 I/V site plays a critical pro-tumoral role in GBM and correlates with a worse prognosis in GBM patients A:I
Glioblastoma
Anti-tumoral: reduction of maturation of oncogenic precursors C:U
Glioblastoma
Reduction of RNA editing at the Q/R site of the GluRB induces loss of Ca2+ homeostasis suggests a role for RNA editing in tumor progression and may provide a molecular model explaining the occurrence of epileptic seizures in association with malignant gliomas. A:I
Glioblastoma
The overexpression of ADARB1 inhibits GBM cell line proliferation A:I
Glioblastoma
A-to-I RNA editing of the SLC22A3 gene is associated with the reduced SLC22A3 transcription and lymph node metastasis in Esophageal Squamous Cell Carcinoma A:I
Esophageal squamous cell carcinoma
ADARB1 is downregulated in In Esophageal Squamous Cell Carcinoma (ESCC). In normal tissue, ADARB1 suppresses tumor growth and induces apoptosis by editing and stabilizing IGFBP7. A:I
Esophageal squamous cell carcinoma
RNA editing inhibits the enzymatic activity of TPH2 splice variants. Deregulated alternative splicing and RNA editing are involved in the etiology of psychiatric diseases, such as suicidal behavior. A:I
Depression disorder
RNA editing inhibits the enzymatic activity of TPH2 splice variants. Deregulated alternative splicing and RNA editing are involved in the etiology of psychiatric diseases, such as suicidal behavior. C:U
Depression disorder
RNA editing inhibits the enzymatic activity of TPH2 splice variants. Deregulated alternative splicing and RNA editing are involved in the etiology of psychiatric diseases, such as suicidal behavior. A:I
Depression disorder
RNA editing inhibits the enzymatic activity of TPH2 splice variants. Deregulated alternative splicing and RNA editing are involved in the etiology of psychiatric diseases, such as suicidal behavior. C:U
Depression disorder
Edited form of RhoQ protein plays an important role in promoting the invasive potential of colorectal cancer A:I
Colorectal cancer
A general decrease in editing activity of the human BLCAP transcript in cancerous tissues A:I
Colorectal cancer
RNA‐editing of Filamin A pre‐mRNA is decreased in human cardiac disease A:I
Cardiac Disease
A general decrease in editing activity of the human BLCAP transcript in cancerous tissues A:I
Bladder cancer
hV1.1 recoded by editing (Ile400) is altered in the intracellular side of the selectivity filter A:I
Behavioral and neurological consequences
RNA-editing enzyme ADAR2 occurs in the majority of ALS cases and causes the death of motor neurons A:I
Amiothrophic Lateral Sclerosis
Defect in the editing of the messenger RNA encoding the GluR2 subunit of glutamate AMPA receptors in ALS patients A:I
Amiothrophic Lateral Sclerosis
The inefficient GluA2 Q/R site-editing by ADAR2 is one cause of motor neuron death in ALS. A:I
Amiothrophic Lateral Sclerosis
Deficiency of RNA editing in Q/R site of the GluA2 induces the loss of Ca2+ homeostasis associated with early onset epilepsy and premature death A:I
Alzheimer
ADAR1 acts as a suppressor of type I interferon signaling and may have a role in the cytoplasmic accumulation of dsRNA originating from genomic repetitive elements. A:I
Aicardi-Goutières syndrome
Splicing mutations affecting either the SH2 or PTPase domain of SHP-1 in motheaten and viable motheaten mice lead to multiple hematopoietic abnormalities, including the overexpansion and accumulation of myelomonocytic populations A:I
Acute Myeloid Leukemia

Publications:

Title Authors Journal Details PubMed Id DOI