Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human APOBEC3G (A3G) belongs to a family of polynucleotide cytidine deaminases. This family includes APOBEC1 and AID, which edit APOB mRNA and antibody gene DNA, respectively. A3G deaminates cytidines to uridines in single-strand DNA and inhibits the replication of human immunodeficiency virus-1, other retroviruses, and retrotransposons. Although the mechanism of A3G-catalyzed DNA deamination has been investigated genetically and biochemically, atomic details are just starting to emerge. Here, we compare the DNA cytidine deaminase activities and NMR structures of two A3G catalytic domain constructs. The longer A3G191-384 protein is considerably more active than the shorter A3G198-384 variant. The longer structure has an alpha1-helix (residues 201-206) that was not apparent in the shorter protein, and it contributes to catalytic activity through interactions with hydrophobic core structures (beta1, beta3, alpha5, and alpha6). Both A3G catalytic domain solution structures have a discontinuous beta2 region that is clearly different from the continuous beta2 strand of another family member, APOBEC2. In addition, the longer A3G191-384 structure revealed part of the N-terminal pseudo-catalytic domain, including the interdomain linker and some of the last alpha-helix. These structured residues (residues 191-196) enabled a novel full-length A3G model by providing physical overlap between the N-terminal pseudo-catalytic domain and the new C-terminal catalytic domain structure. Contrary to predictions, this structurally constrained model suggested that the two domains are tethered by structured residues and that the N- and C-terminal beta2 regions are too distant from each other to participate in this interaction.
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PMID:An extended structure of the APOBEC3G catalytic domain suggests a unique holoenzyme model. 1938 8

We showed that nucleotide sequences coding for linear B-cell epitopes of human immunodeficiency virus type 1 (HIV1) gp120 protein are enriched with codons containing cytosine and guanine in their first and second codon positions. Guanine and cytosine are the most mutable nucleotides in HIV1 genes (due to APOBEC3 and APOBEC1 editing of viral DNA and RNA, respectively, as well as due to reverse transcriptase preference to incorporate 8-oxo-G against C). We introduced all the possible G to A, C to U, C to A and G to U single nonsynonymous nucleotide mutations in gp120 coding region from the HIV1 reference strain. The BepiPred algorithm (www.cbs.dtu.dk/services/BepiPred) was used for the linear B-cell epitopes predictions. Results of this "in-silico directed mutagenesis" showed that: (i) single nonsynonymous G to A transitions will cause partial or complete destruction of linear epitopes in 18% of 229 possible cases; (ii) single nonsynonymous C to U transitions will cause partial or complete destruction of linear epitopes in 58% of 142 possible cases; (iii) single nonsynonymous C to A transversions will cause partial or complete destruction of linear epitopes in 28% of 184 possible cases; (iv) single nonsynonymous G to U transversions will cause partial or complete destruction of linear epitopes in 37% of 240 possible cases. Moreover, single transition of C to U direction leading to amino acid replacement inside an epitope will cause partial or complete destruction of this epitope at a probability of 98%.
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PMID:Mutational pressure makes HIV1 gp120 linear B-cell epitopes shorter and may lead to their disappearance. 2012 70

The ability of mammalian cytidine deaminases encoded by the APOBEC3 (A3) genes to restrict a broad number of endogenous retroelements and exogenous retroviruses, including murine leukemia virus and human immunodeficiency virus (HIV)-1, is now well established. The RNA editing family member apolipoprotein B (apo B)-editing catalytic subunit 1 (APOBEC1; A1) from a variety of mammalian species, a protein involved in lipid transport and which mediates C-U deamination of mRNA for apo B, has also been shown to modify a range of exogenous retroviruses, but its activity against endogenous retroelements remains unclear. Here, we show in cell culture-based retrotransposition assays that A1 family proteins from multiple mammalian species can also reduce the mobility and infectivity potential of LINE-1 (long interspersed nucleotide sequence-1, L1) and long-terminal repeats (LTRs) retrotransposons (or endogenous retroviruses), such as murine intracisternal A-particle (IAP) and MusD sequences. The anti-L1 activity of A1 was mainly mediated by a deamination-independent mechanism, and was not affected by subcellular localization of the proteins. In contrast, the inhibition of LTR-retrotransposons appeared to require the deaminase activity of A1 proteins. Thus, the AID/APOBEC family proteins including A1s employ multiple mechanisms to regulate the mobility of autonomous retrotransposons in several mammalian species.
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PMID:Intrinsic restriction activity by apolipoprotein B mRNA editing enzyme APOBEC1 against the mobility of autonomous retrotransposons. 2139 38

Apolipoprotein B (apo B) messenger RNA (mRNA)-editing, catalytic polypeptide (APOBEC) cytidine deaminases (CDAs), which can insert mutations into DNA and/or RNA as a result of their ability to deaminate cytidine (C) to uridine (U), originated from a branch of the zinc-dependent deaminase superfamily at the beginning of vertebrate radiation. The ability of mammalian CDAs encoded by the APOBEC3 genes to restrict a broad number of endogenous retroelements and exogenous retroviruses, including human immunodeficiency virus-1, is well established. Furthermore, APOBEC1 from a variety of mammalian species, which mediates the C-to-U deamination of apo B mRNA, a protein involved in lipid transport, also has a role in controlling mobile elements. A large portion of the mammalian genome is derived from ancient transposable elements. Retroelements, transported by an intracellular copy-and-paste process involving an RNA intermediate, constitute the majority of these mobile genetic elements. Endogenous retroviruses are long-terminal repeat (LTR)-type retroelements that account for approximately 10% of human and murine genomic DNA. Non-LTR members are present in extremely high copy numbers, with approximately 40% of the human and murine genomes consisting of long-interspersed nuclear element-1 (L1). These L1 elements modify mammalian genomes not only through insertions but also by the indirect replication of non-autonomous retrotransposons. As expected, vertebrate intrinsic immunity has evolved to support a balance between retroelement insertions that cause deleterious gene disruptions and those that confer beneficial genetic diversity. This review discusses the current understanding of the mechanism of action of APOBEC CDAs and their role in controlling retroviruses and retroelements.
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PMID:Apolipoprotein B mRNA-editing, catalytic polypeptide cytidine deaminases and retroviral restriction. 2254 84

The activation-induced deaminase (AID)/APOBEC cytidine deaminases participate in a diversity of biological processes from the regulation of protein expression to embryonic development and host defenses. In its classical role, AID mutates germline-encoded sequences of B cell receptors, a key aspect of adaptive immunity, and APOBEC1, mutates apoprotein B pre-mRNA, yielding two isoforms important for cellular function and plasma lipid metabolism. Investigations over the last ten years have uncovered a role of the APOBEC superfamily in intrinsic immunity against viruses and innate immunity against viral infection by deamination and mutation of viral genomes. Further, discovery in the area of human immunodeficiency virus (HIV) infection revealed that the HIV viral infectivity factor protein interacts with APOBEC3G, targeting it for proteosomal degradation, overriding its antiviral function. More recently, our and others' work have uncovered that the AID and APOBEC cytidine deaminase family members have an even more direct link between activity against viral infection and induction and shaping of adaptive immunity than previously thought, including that of antigen processing for cytotoxic T lymphocyte activity and natural killer cell activation. Newly ascribed functions of these cytodine deaminases will be discussed, including their newly identified roles in adaptive immunity, epigenetic regulation, and cell differentiation. Herein this review we discuss AID and APOBEC cytodine deaminases as a link between innate and adaptive immunity uncovered by recent studies.
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PMID:AID and APOBECs span the gap between innate and adaptive immunity. 2535 38

APOBEC3s (A3s) are single-stranded DNA cytosine deaminases that provide innate immune defences against retroviruses and mobile elements. A3s are specific to eutherian mammals because no direct homologs exist at the syntenic genomic locus in metatherian (marsupial) or prototherian (monotreme) mammals. However, the A3s in these species have the likely evolutionary precursors, the antibody gene deaminase AID and the RNA/DNA editing enzyme APOBEC1 (A1). Here, we used cell culture-based assays to determine whether opossum A1 restricts the infectivity of retroviruses including human immunodeficiency virus type 1 (HIV-1) and the mobility of LTR/non-LTR retrotransposons. Opossum A1 partially inhibited HIV-1, as well as simian immunodeficiency virus (SIV), murine leukemia virus (MLV), and the retrotransposon MusD. The mechanism of inhibition required catalytic activity, except for human LINE1 (L1) restriction, which was deamination-independent. These results indicate that opossum A1 functions as an innate barrier to infection by retroviruses such as HIV-1, and controls LTR/non-LTR retrotransposition in marsupials.
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PMID:Opossum APOBEC1 is a DNA mutator with retrovirus and retroelement restriction activity. 2842 55


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