7c0j
From Proteopedia
Crystal structure of chimeric mutant of GH5 in complex with Z-DNA
Structural highlights
DiseaseDSRAD_HUMAN Defects in ADAR are a cause of dyschromatosis symmetrical hereditaria (DSH) [MIM:127400; also known as reticulate acropigmentation of Dohi. DSH is a pigmentary genodermatosis of autosomal dominant inheritance characterized by a mixture of hyperpigmented and hypopigmented macules distributed on the dorsal parts of the hands and feet.[1] [2] [3] FunctionDSRAD_HUMAN Catalyzes the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) referred to as A-to-I RNA editing. This may affect gene expression and function in a number of ways that include mRNA translation by changing codons and hence the amino acid sequence of proteins; pre-mRNA splicing by altering splice site recognition sequences; RNA stability by changing sequences involved in nuclease recognition; genetic stability in the case of RNA virus genomes by changing sequences during viral RNA replication; and RNA structure-dependent activities such as microRNA production or targeting or protein-RNA interactions. Can edit both viral and cellular RNAs and can edit RNAs at multiple sites (hyper-editing) or at specific sites (site-specific editing). Its cellular RNA substrates include: bladder cancer-associated protein (BLCAP), neurotransmitter receptors for glutamate (GRIA2) and serotonin (HTR2C) and GABA receptor (GABRA3). Site-specific RNA editing of transcripts encoding these proteins results in amino acid substitutions which consequently alters their functional activities. Exhibits low-level editing at the GRIA2 Q/R site, but edits efficiently at the R/G site and HOTSPOT1. Its viral RNA substrates include: hepatitis C virus (HCV), vesicular stomatitis virus (VSV), measles virus (MV), hepatitis delta virus (HDV), and human immunodeficiency virus type 1 (HIV-1). Exhibits either a proviral (HDV, MV, VSV and HIV-1) or an antiviral effect (HCV) and this can be editing-dependent (HDV and HCV), editing-independent (VSV and MV) or both (HIV-1). Impairs HCV replication via RNA editing at multiple sites. Enhances the replication of MV, VSV and HIV-1 through an editing-independent mechanism via suppression of EIF2AK2/PKR activation and function. Stimulates both the release and infectivity of HIV-1 viral particles by an editing-dependent mechanism where it associates with viral RNAs and edits adenosines in the 5'UTR and the Rev and Tat coding sequence. Can enhance viral replication of HDV via A-to-I editing at a site designated as amber/W, thereby changing an UAG amber stop codon to an UIG tryptophan (W) codon that permits synthesis of the large delta antigen (L-HDAg) which has a key role in the assembly of viral particles. However, high levels of ADAR1 inhibit HDV replication.[4] [5] [6] [7] [8] [9] [10] [11] [12] [13] H5_CHICK Histone H5 performs the same function as H1, being necessary for the condensation of nucleosome chains into higher order structures, and replaces histone H1 in certain cells. Publication Abstract from PubMedLeft-handed Z-DNA is radically different from the most common right-handed B-DNA and can be stabilized by interactions with the Zalpha domain, which is found in a group of proteins, such as human ADAR1 and viral E3L proteins. It is well-known that most Zalpha domains bind to Z-DNA in a conformation-specific manner and induce rapid B-Z transition in physiological conditions. Although many structural and biochemical studies have identified the detailed interactions between the Zalpha domain and Z-DNA, little is known about the molecular basis of the B-Z transition process. In this study, we successfully converted the B-Z transition-defective Zalpha domain, vvZalphaE3L, into a B-Z converter by improving B-DNA binding ability, suggesting that B-DNA binding is involved in the B-Z transition. In addition, we engineered the canonical B-DNA binding protein GH5 into a Zalpha-like protein having both Z-DNA binding and B-Z transition activities by introducing Z-DNA interacting residues. Crystal structures of these mutants of vvZalphaE3L and GH5 complexed with Z-DNA confirmed the significance of conserved Z-DNA binding interactions. Altogether, our results provide molecular insight into how Zalpha domains obtain unusual conformational specificity and induce the B-Z transition. Dual conformational recognition by Z-DNA binding protein is important for the B-Z transition process.,Park C, Zheng X, Park CY, Kim J, Lee SK, Won H, Choi J, Kim YG, Choi HJ Nucleic Acids Res. 2020 Dec 16;48(22):12957-12971. doi: 10.1093/nar/gkaa1115. PMID:33245772[14] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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