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)

The virally encoded proteases from human immunodeficiency virus (HIV) and avian myeloblastosis virus (AMV) have been compared relative to their ability to hydrolyze a variant of the three-domain Pseudomonas exotoxin, PE66. This exotoxin derivative, missing domain I and referred to as LysPE40, is made up of a 13-kilodalton NH2-terminal translocation domain II connected by a segment of 40 amino acids to enzyme domain III of the toxin, a 23-kilodalton ADP-ribosyltransferase. HIV protease hydrolyzes two peptide bonds in LysPE40, a Leu-Leu bond in the interdomain region and a Leu-Ala bond in a nonstructured region three residues in from the NH2-terminus. Neither of these sites is cleaved by the AMV enzyme; hydrolysis occurs, instead, at an Asp-Val bond in another part of the interdomain segment and at a Leu-Thr bond in the NH2-terminal region of domain II. Synthetic peptides corresponding to these cleavage sites are hydrolyzed by the individual proteases with the same specificity displayed toward the protein substrate. Peptide substrates for one protease are neither substrates nor competitive inhibitors for the other. A potent inhibitor of HIV type 1 protease was more than 3 orders of magnitude less active toward the AMV enzyme. These results suggest that although the crystallographic models of Rous sarcoma virus protease (an enzyme nearly identical to the AMV enzyme) and HIV type 1 protease show a high degree of similarity, there exist structural differences between these retroviral proteases that are clearly reflected by their kinetic properties.
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PMID:Proteases from human immunodeficiency virus and avian myeloblastosis virus show distinct specificities in hydrolysis of multidomain protein substrates. 216 35

The crystal structures of the proteases (PRs) encoded by the Rous sarcoma virus (RSV) and the human immunodeficiency virus (HIV) have been compared. The crystallographic monomer of HIV PR superimposes on the two crystallographically independent subunits of the RSV PR dimer with root mean square deviations of 1.45 and 1.55 A for 86 and 88 common C alpha atoms, respectively. There is a conserved structural core consisting of seven beta-strands forming two perpendicular layers, a helix, and the amino- and carboxyl-terminal beta-strands. PRs from related retroviruses fold into similar structures with surface turns of variable length between the beta-strands. Both HIV and RSV PR dimers have significant subunit-subunit interactions in three regions: the "firemen's grip" at the active site; the salt bridges involving Arg8, Asp29, and Arg87 of HIV PR; and the termini of the two subunits, which form a four-stranded antiparallel beta-sheet. The specific interactions of the termini differ in the two PRs. The carboxyl termini, residues 96-99 of HIV PR and residues 119-124 of RSV PR, contribute approximately 50% of the intersubunit ionic and hydrogen bond interactions and approximately 45% of the buried surface area involved in dimer formation. This information may be useful in the design of site-directed mutations or inhibitors of dimer formation.
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PMID:Comparison of the crystal structures and intersubunit interactions of human immunodeficiency and Rous sarcoma virus proteases. 216 50

We investigated whether Rous sarcoma virus (RSV) infects cells through a pH-independent or a low-pH-dependent pathway. To do this, the effects of lysosomotropic agents and acid pretreatment on RSV infectivity of, and fusion with, chicken embryo fibroblasts (CEFs) were studied. High concentrations of lysosomotropic agents (ammonium chloride and monensin) did not inhibit virus infectivity: equal titers of RSV were produced in the presence and absence of these agents. Similarly, low-pH pretreatment did not inhibit RSV infectivity. In parallel experiments, lysosomotropic agents and acid pretreatment completely abolished the ability of influenza virus to infect CEFs. To monitor the fusion activity of RSV directly, the viral membrane was labeled with the fluorescent lipid probe octadecyl rhodamine at a self-quenching concentration. Upon fusion with a host cell, the probe is diluted in the cell membrane, resulting in fluorescence dequenching (D. Hoekstra, T. de Boer, K. Klappe, and J. Wilschut, Biochemistry 23:5675-5681, 1984). In this assay, fusion of RSV with CEFs was found to occur in both a time-dependent and a strictly temperature-dependent fashion. No fusion occurred unless cells with prebound virus were warmed to temperatures greater than 20 degrees C. Fusion, but not binding, was abolished if virus was pretreated with low concentrations of glutaraldehyde. High concentrations of ammonium chloride had no effect on fusion of RSV with CEFs but greatly diminished the ability of influenza virus and Semliki Forest virus to fuse with CEFs. Similarly, acid pretreatment of RSV had no effect on fusion with CEFs while markedly inhibiting fusion of both influenza and Semliki Forest viruses. Collectively, our results show that RSV fusion with and hence infection of CEFs does not require exposure of the virus to low pH. In this respect, RSV resembles another retrovirus, human immunodeficiency virus.
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PMID:Fusion of Rous sarcoma virus with host cells does not require exposure to low pH. 216 89

Based on precedents from other retroviruses, the precursor of the human immunodeficiency virus (HIV-1) reverse transcriptase is predicted to be a polyprotein with a relative molecular mass (Mr) of 160,000 (160K) encoded by both the viral pol gene and the upstream gag gene. These two genes lie in different translational reading frames, with the 3' end of gag overlapping the 5' end of pol by 205 or 241 nucleotides. Thus, production of the gag-pol fusion protein would require either messenger RNA processing or translational frameshifting. The latter mechanism has been shown in the synthesis of the gag-pol proteins of two other retroviruses, Rous sarcoma virus (RSV) and mouse mammary tumour virus (MMTV). Here we report that translation of HIV-1 RNA synthesized in vitro by SP6 RNA polymerase yields significant amounts of a gag-pol fusion protein, indicating that efficient ribosomal frameshifting also occurs within the HIV-1 gag-pol overlap region. Site-directed mutagenesis and amino-acid sequencing localized the site of frameshifting to a UUA leucine codon near the 5' end of the overlap.
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PMID:Characterization of ribosomal frameshifting in HIV-1 gag-pol expression. 244 6

The nucleotide sequence of the human spumaretrovirus (HSRV) genome was determined. The 5' long terminal repeat region was analyzed by strong stop cDNA synthesis and S1 nuclease mapping. The length of the RU5 region was determined and found to be 346 nucleotides long. The 5' long terminal repeat is 1,123 base pairs long and is bound by an 18-base-pair primer-binding site complementary to the 3' end of mammalian lysine-1,2-specific tRNA. Open reading frames for gag and pol genes were identified. Surprisingly, the HSRV gag protein does not contain the cysteine motif of the nucleic acid-binding proteins found in and typical of all other retroviral gag proteins; instead the HSRV gag gene encodes a strongly basic protein reminiscent of those of hepatitis B virus and retrotransposons. The carboxy-terminal part of the HSRV gag gene products encodes a protease domain. The pol gene overlaps the gag gene and is postulated to be synthesized as a gag/pol precursor via translational frameshifting analogous to that of Rous sarcoma virus, with 7 nucleotides immediately upstream of the termination codons of gag conserved between the two viral genomes. The HSRV pol gene is 2,730 nucleotides long, and its deduced protein sequence is readily subdivided into three well-conserved domains, the reverse transcriptase, the RNase H, and the integrase. Although the degree of homology of the HSRV reverse transcriptase domain is highest to that of murine leukemia virus, the HSRV genomic organization is more similar to that of human and simian immunodeficiency viruses. The data justify classifying the spumaretroviruses as a third subfamily of Retroviridae.
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PMID:Analysis of the primary structure of the long terminal repeat and the gag and pol genes of the human spumaretrovirus. 245 55

Retroviral gag, pol and env gene products are translated as precursor polyproteins, which are cleaved by virus-encoded proteases to produce the mature proteins found in virions. On the basis of the conserved Asp-Thr/Ser-Gly sequence at the putative protease active sites, and other biochemical evidence, retroviral proteases have been predicted to be in the family of pepsin-like aspartic proteases. It has been suggested that aspartic proteases evolved from a smaller, dimeric ancestral protein, and a recent model of the human immunodeficiency virus (HIV) protease postulated that a symmetric dimer of this enzyme is equivalent to a pepsin-like aspartic protease. We have now determined the crystal structure of Rous sarcoma virus (RSV) protease at 3-A resolution and find it is dimeric and has a structure similar to aspartic proteases. This structure should provide a useful basis for the modelling of the structures of other retroviral proteases, such as that of HIV, and also for the rational design of protease inhibitors as potential antiviral drugs.
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PMID:Crystal structure of a retroviral protease proves relationship to aspartic protease family. 253 2

The human immunodeficiency virus (HIV-1) encodes a protease that is essential for viral replication and is a member of the aspartic protease family. The recently determined three-dimensional structure of the related protease from Rous sarcoma virus has been used to model the smaller HIV-1 dimer. The active site has been analyzed by comparison to the structure of the aspartic protease, rhizopuspepsin, complexed with a peptide inhibitor. The HIV-1 protease is predicted to interact with seven residues of the protein substrate. This information can be used to design protease inhibitors and possible antiviral drugs.
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PMID:Molecular modeling of the HIV-1 protease and its substrate binding site. 253 31

To study the effect of poliovirus protein 2A on cellular RNA translation, the tat control system of human immunodeficiency virus (HIV) was used. Protein 2A was expressed from a plasmid construct (pHIV/2A) incorporating the HIV long terminal repeat. Protein synthesis was measured by using chloramphenicol acetyltransferase as a reporter gene driven by the Rous sarcoma virus long terminal repeat. When HIV/2A was cotransfected with the reporter, addition of a tat-producing plasmid caused at least a 50-fold drop in chloramphenicol acetyltransferase synthesis. A HeLa cell line carrying HIV/2A was established. In it, tat expression caused more than a 10-fold drop in chloramphenicol acetyltransferase synthesis from the reporter plasmid. Furthermore, 2A induction by tat caused cleavage of the cellular translation factor P220, a part of eukaryotic translation initiation factor 4F. Thus protein 2A can, by itself, carry out the inhibition of cellular protein synthesis characteristic of a poliovirus infection. Also, the HIV tat activation provides a very effective method to control gene expression in mammalian cells.
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PMID:Human immunodeficiency virus tat-activated expression of poliovirus protein 2A inhibits mRNA translation. 253 33

The long terminal repeats (LTRs) of the human immunodeficiency virus (HIV) the Rous sarcoma virus (RSV) and the copia Drosophila retrotransposon were compared in their capacity to direct expression of the bacterial cat (chloramphenicol acetyltransferase) gene in human, murine, and Drosophila cell lines. The results indicate that HIV and RSV LTR expression is post transcriptionally repressed in the Drosophila cells while copia LTR expression is post-transcriptionally repressed in the human and murine cells.
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PMID:HIV-1 expression is posttranscriptionally repressed in Drosophila cells. 254 51

Protein myristoylation was first discovered in the catalytic subunit of adenosine 3',5'-cyclic monophosphate-dependent protein kinase. Subsequently, various cellular and viral myristoylated proteins were detected. In each case, the myristoyl moiety was found in an amide linkage with the amino terminal glycine residue of the modified proteins. The biological functions of protein myristoylation of various cellular protein, oncogene product, and viral structural proteins have been studied by many biochemists. Two of the most thoroughly studies myristoylated proteins are the transforming protein of Rous sarcoma virus, pp60v-src, and the proto-oncogene product, pp60c-src. Deletion, modification of the first 14 NH2-terminal amino acid of pp60v-src, or chemical antimyristoylation of the protein with N-myristoyl glycinal diethylacetal does not affect intrinsic tyrosine src-kinase activity, but prevents myristoylation and membrane association, and abolishes the transforming activity of the protein. Protein myristoylations of some viral structural proteins were also studied by many investigators, and X-ray crystallographic studies of poliovirus suggest that myristate moiety may play a central role in capsid assembly. Recently, human immunodeficiency virus, HIV-I, process a myristoylated p17gag protein, which is proteolytically derived from the NH2-terminus of a gag precursor protein, and its myristate moiety may be important for virus assembly. In this review, we detailed recent studies of the protein myristoylation in cellular regulation and virus proliferation.
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PMID:[Function of protein myristoylation in cellular regulation and viral proliferation]. 254 55


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