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51.
52.
N-myristoylation determines dual targeting of mammalian NADH-cytochrome b5 reductase to ER and mitochondrial outer membranes by a mechanism of kinetic partitioning 总被引:3,自引:0,他引:3
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Colombo S Longhi R Alcaro S Ortuso F Sprocati T Flora A Borgese N 《The Journal of cell biology》2005,168(5):735-745
Mammalian NADH-cytochrome b5 reductase (b5R) is an N-myristoylated protein that is dually targeted to ER and mitochondrial outer membranes. The N-linked myristate is not required for anchorage to membranes because a stretch of hydrophobic amino acids close to the NH2 terminus guarantees a tight interaction of the protein with the phospholipid bilayer. Instead, the fatty acid is required for targeting of b5R to mitochondria because a nonmyristoylated mutant is exclusively localized to the ER. Here, we have investigated the mechanism by which N-linked myristate affects b5R targeting. We find that myristoylation interferes with interaction of the nascent chain with signal recognition particle, so that a portion of the nascent chains escapes from cotranslational integration into the ER and can be post-translationally targeted to the mitochondrial outer membrane. Thus, competition between two cotranslational events, binding of signal recognition particle and modification by N-myristoylation, determines the site of translation and the localization of b5R. 相似文献
53.
The respiratory sensation and some routine cardiorespiratory parameters were studied on native Highlanders from the Argentine
Andes and on Lowlanders from Europe, already tested during previous high altitude expeditions. The tests were performed at
various altitude levels from 2688m e.i., the village altitude for Highlanders, to 5600m during an expedition to Mt. Aconcagua
(6990m). At rest, the perception of 4 external inspiratory resistive loads (ranged between 2.5 and 13 cm.H2O.L-1.s) can allow
us to fix by discrimination the sensitivity index P(A) independently of response bias (B) according to Sensory Decision Theory
(SDT). The Andean highlanders did not experience the respiratory sensation at the same limits as the European lowlanders well
adaptated to high altitude. At higher altitudes than their village altitude, their respiratory sensation presented a lower
threshold of perception and a weaker discrimination which might be partly explained by the evolution of some parameters of
their cardio-respiratory function when altitude increased. Indeed, in response to high altitude hypoxia (5600m), they increased
their respiratory frequency and not their minuteventilation or mouth pressure. This chosen ventilatory pattern was opposite
to the one chosen by the Lowlanders and did not allow for sufficient adaptation to a more important altitude hypoxia than
that of their village altitude. In conclusion, the Andean highlanders wellbeing adapted to their village altitude, exhibited
a difficult acclimatization to higher altitudes which might be due to the characteristics of their respiratory sensation.
These results might explain their weak physical performances during ascent to the Mt. Aconcagua summit in spite of special
training. 相似文献
54.
Variant forms of a group I intron in nuclear small-subunit rRNA genes of the marine red alga Porphyra spiralis var. amplifolia 总被引:3,自引:0,他引:3
A group IC1 intron occurs in nuclear small-subunit (18S) ribosomal RNA (SSU
rRNA) genes of the marine red alga Porphyra spiralis var. amplifolia. This
intron occurs at the same position as the self- splicing group IC1 introns
in nuclear SSU rDNAs of the fungus Pneumocystis carinii and in the green
alga Chlorella ellipsoidea and shares sequence identity with the
Pneumocystis carinii intron in domains L1, P1, P2, and L2, outside the
conserved core. Three size variants, differing in amount of sequence in L1,
exist and are differentially distributed in geographically distinct
populations. Preliminary data suggest that the largest variant can
self-splice in vitro. Short open reading frames are present but do not
correspond to known genes. Repeated nucleotide motifs, reminiscent of
duplicated target sites of transposons or Alu elements, are associated with
the intron and with one of the variant forms of L1. Insertions are present
in nuclear SSU rDNAs of several other Porphyra species and of the red alga
Bangia atropurpurea; insertionless rDNA variants also occur in several
Porphyra species. Our observations are most readily explained by intron
mobility, although it remains unclear how transfer could have been mediated
between genomes of organisms as ecologically diverse as marine red algae,
freshwater green algae, and a mammalian-pathogenic fungus.
相似文献
55.
Angela Corona Rita Meleddu Francesca Esposito Simona Distinto Giulia Bianco Takashi Masaoka Elias Maccioni Luis Menéndez-Arias Stefano Alcaro Stuart F. J. Le Grice Enzo Tramontano 《PloS one》2016,11(1)
The DNA polymerase and ribonuclease H (RNase H) activities of human immunodeficiency virus type 1 (HIV-1) are needed for the replication of the viral genome and are validated drug targets. However, there are no approved drugs inhibiting RNase H and the efficiency of DNA polymerase inhibitors can be diminished by the presence of drug resistance mutations. In this context, drugs inhibiting both activities could represent a significant advance towards better anti-HIV therapies. We report on the mechanisms of allosteric inhibition of a newly synthesized isatin-based compound designated as RMNC6 that showed IC50 values of 1.4 and 9.8 μM on HIV-1 RT-associated RNase H and polymerase activities, respectively. Blind docking studies predict that RMNC6 could bind two different pockets in the RT: one in the DNA polymerase domain (partially overlapping the non-nucleoside RT inhibitor [NNRTI] binding pocket), and a second one close to the RNase H active site. Enzymatic studies showed that RMNC6 interferes with efavirenz (an approved NNRTI) in its binding to the RT polymerase domain, although NNRTI resistance-associated mutations such as K103N, Y181C and Y188L had a minor impact on RT susceptibility to RMNC6. In addition, despite being naturally resistant to NNRTIs, the polymerase activity of HIV-1 group O RT was efficiently inhibited by RMNC6. The compound was also an inhibitor of the RNase H activity of wild-type HIV-1 group O RT, although we observed a 6.5-fold increase in the IC50 in comparison with the prototypic HIV-1 group M subtype B enzyme. Mutagenesis studies showed that RT RNase H domain residues Asn474 and Tyr501, and in a lesser extent Ala502 and Ala508, are critical for RMNC6 inhibition of the endonuclease activity of the RT, without affecting its DNA polymerization activity. Our results show that RMNC6 acts as a dual inhibitor with allosteric sites in the DNA polymerase and the RNase H domains of HIV-1 RT. 相似文献
56.
József Prechl Krisztián Papp Zoltán Hérincs Hajna Péterfy Veronika Lóránd Zoltán Szittner Andone Estonba Paolo Rovero Ilaria Paolini Jokin del Amo Maria Uribarri Maria Claudia Alcaro Otsanda Ruiz-Larra?aga Paola Migliorini László Czirják 《PloS one》2016,11(3)
Systemic lupus erythematosus is a chronic autoimmune disease with multifactorial ethiopathogenesis. The complement system is involved in both the early and late stages of disease development and organ damage. To better understand autoantibody mediated complement consumption we examined ex vivo immune complex formation on autoantigen arrays. We recruited patients with SLE (n = 211), with other systemic autoimmune diseases (n = 65) and non-autoimmune control subjects (n = 149). Standard clinical and laboratory data were collected and serum complement levels were determined. The genotype of SNP rs1143679 in the ITGAM gene was also determined. Ex vivo formation of immune complexes, with respect to IgM, IgG, complement C4 and C3 binding, was examined using a functional immunoassay on autoantigen microarray comprising nucleic acids, proteins and lipids. Complement consumption of nucleic acids increased upon binding of IgM and IgG even when serum complement levels were decreased due to consumption in SLE patients. A negative correlation between serum complement levels and ex vivo complement deposition on nucleic acid autoantigens is demonstrated. On the contrary, complement deposition on tested protein and lipid autoantigens showed positive correlation with C4 levels. Genetic analysis revealed that the non-synonymous variant rs1143679 in complement receptor type 3 is associated with an increased production of anti-dsDNA IgG antibodies. Notwithstanding, homozygous carriers of the previously reported susceptible allele (AA) had lower levels of dsDNA specific IgM among SLE patients. Both the non-synonymous variant rs1143679 and the high ratio of nucleic acid specific IgG/IgM were associated with multiple organ involvement. In summary, secondary complement deficiency in SLE does not impair opsonization of nucleic-acid-containing autoantigens but does affect other antigens and potentially other complement dependent processes. Dysfunction of the receptor recognizing complement opsonized immune complexes promotes the development of class-switched autoantibodies targeting nucleic acids. 相似文献
57.
58.
59.
Alcaro S Scipione L Ortuso F Posca S Rispoli V Rotiroti D 《Bioorganic & medicinal chemistry letters》2002,12(20):2899-2905
Pivaloyl-choline iodide 1 interactions with acetylcholinesterase (AChE) have been studied by theoretical and enzymatic methods. An integrated computational approach has clearly shown a substrate rather than inhibitory profile for 1. Enzymatic experiments have also supported the same theoretical conclusion indicating that AChE was able to hydrolyze 1 to choline. 相似文献
60.
Alcaro S Tafi A Ortuso F Woźniak LA Gács-Baitz E Botta M 《Bioorganic & medicinal chemistry letters》2001,11(17):2273-2277
A preliminary MMFF implementation of selenium atom parameters necessary to model the nucleoside 1 is reported. X-ray structures of two compounds 1 and 2 have been used as references. Ab initio methods have been adopted for checking torsional energy profile and charge distribution. Monte Carlo calculations and energy minimization in solvation complete the conformational search. 相似文献