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331.
The regulatory gene areA mediating nitrogen metabolite repression in Aspergillus nidulans. Mutations affecting specificity of gene activation alter a loop residue of a putative zinc finger. 总被引:20,自引:5,他引:20 下载免费PDF全文
B Kudla M X Caddick T Langdon N M Martinez-Rossi C F Bennett S Sibley R W Davies H N Arst Jr 《The EMBO journal》1990,9(5):1355-1364
332.
333.
Aphanothece halophytica, a halophilic cyanobacterium capable of growing in saturated NaCl, accumulates high intracellular concentrations of glycinebetaine in response to increasing environmental NaCl. In this organism, intracellular levels of K+ rise dramatically with increasing external NaCl before an increase in glycinebetaine can be detected. Glycinebetaine synthesis requires three S-adenosylmethionine (AdoMet)-mediated transmethylations; each transmethylation reaction generates one molecule of the transmethylation inhibitor S-adenosylhomocysteine (AdoHcy). Thus, glycinebetaine synthesis should require continued removal of AdoHcy. In A. halophytica, catabolism of AdoHcy was shown to occur via the reversible reaction catalyzed by AdoHcy hydrolase (EC 3.3.1.1). Activity of AdoHcy hydrolase in the direction of synthesis of AdoHcy was inhibited by 0.4 M KCl in this organism. On the other hand, activity of AdoHcy hydrolase in the direction of AdoHcy hydrolysis was unaffected by 0.4 M KCl. Glycinebetaine increased synthesis of AdoHcy in the presence of 0.4 KCl, but had no effect on AdoHcy hydrolysis. Based upon these results, a mechanism is proposed for the regulation of glycinebetaine synthesis by K+ and glycinebetaine in A. halophytica. According to this mechanism, the regulatory response would be initiated by a K+-induced shift in the AdoMet/AdoHcy ratio.Abbreviations AdoMet
S-adenosylmethionine
- AdoHcy
S-adenosyl homocysteine 相似文献
334.
335.
Lovett JL Marchesini N Moreno SN Sibley LD 《The Journal of biological chemistry》2002,277(29):25870-25876
Calcium-mediated microneme secretion in Toxoplasma gondii is stimulated by contact with host cells, resulting in the discharge of adhesins that mediate attachment. The intracellular source of calcium and the signaling pathway(s) triggering release have not been characterized, prompting our search for mediators of calcium signaling and microneme secretion in T. gondii. We identified two stimuli of microneme secretion, ryanodine and caffeine, which enhanced release of calcium from parasite intracellular stores. Ethanol, a previously characterized trigger of microneme secretion, stimulated an increase in parasite inositol 1,4,5-triphosphate, implying that this second messenger may mediate intracellular calcium release. Consistent with this observation, xestospongin C, an inositol 1,4,5-triphosphate receptor antagonist, inhibited microneme secretion and blocked parasite attachment and invasion of host cells. Collectively, these results suggest that T. gondii possess an intracellular calcium release channel with properties of the inositol 1,4,5-triphosphate/ryanodine receptor superfamily. Intracellular calcium channels, previously studied almost exclusively in multicellular animals, appear to also be critical to the control of parasite calcium during the initial steps of host cell entry. 相似文献
336.
8-Bromo-adenosine (8-Br-adenosine) stimulates CG production in the JAr choriocarcinoma cell line. Because production of the alpha and beta CG subunits is coupled to the differentiation state of the trophoblasts, we compared the effect of adenosine on CG synthesis in the choriocarcinoma cell line with that in cytotrophoblast cells isolated from normal human term placenta. 8-Br-adenosine stimulated CG production by 5- to 6-fold in both cell types, whereas 8-Br-guanosine had no effect, demonstrating specificity for adenine-containing derivatives. The ratio of CG alpha to CG beta production in JAr cells was 2:1 in the absence or presence of 8-Br-adenosine, whereas in cytotrophoblasts the ratio was 14:1 in controls, but decreased to 3:1 with 8-Br-adenosine. The latter is attributed to an enhanced production of the beta-sub-unit. Immunocytochemistry revealed that CG alpha and CG beta were only expressed in about 4% of JAr cells, and 8-Br-adenosine stimulated the number of positive cells 2- to 4-fold. Since 8-Br-adenosine also inhibited the division of JAr cells, the data suggest that it stimulates CG expression by promoting exit of a population of the cells from the cell cycle. In nondividing placenta-derived cytotrophoblasts, 8-Br-adenosine affects a later step in the differentiation pathway, resulting in a greater effect on the beta- than the alpha-subunit. Thus, our data further support the hypothesis that regulation of CG biosynthesis is linked to differentiation of the trophoblast. 相似文献
337.
Yoon Namkung Concetta Dipace Jonathan A. Javitch David R. Sibley 《The Journal of biological chemistry》2009,284(22):15038-15051
We investigated the role of G protein-coupled receptor kinase
(GRK)-mediated phosphorylation in agonist-induced desensitization, arrestin
association, endocytosis, and intracellular trafficking of the D2
dopamine receptor (DAR). Agonist activation of D2 DARs results in
rapid and sustained receptor phosphorylation that is solely mediated by GRKs.
A survey of GRKs revealed that only GRK2 or GRK3 promotes D2 DAR
phosphorylation. Mutational analyses resulted in the identification of eight
serine/threonine residues within the third cytoplasmic loop of the receptor
that are phosphorylated by GRK2/3. Simultaneous mutation of these eight
residues results in a receptor construct, GRK(-), that is completely devoid of
agonist-promoted GRK-mediated receptor phosphorylation. We found that both
wild-type (WT) and GRK(-) receptors underwent a similar degree of
agonist-induced desensitization as assessed using [35S]GTPγS
binding assays. Similarly, both receptor constructs internalized to the same
extent in response to agonist treatment. Furthermore, using bioluminescence
resonance energy transfer assays to directly assess receptor association with
arrestin3, we found no differences between the WT and GRK(-) receptors. Thus,
phosphorylation is not required for arrestin-receptor association or
agonist-induced desensitization or internalization. In contrast, when we
examined recycling of the D2 DARs to the cell surface, subsequent
to agonist-induced endocytosis, the GRK(-) construct exhibited less recycling
in comparison with the WT receptor. This impairment appears to be due to a
greater propensity of the GRK(-) receptors to down-regulate once internalized.
In contrast, if the receptor is highly phosphorylated, then receptor recycling
is promoted. These results reveal a novel role for GRK-mediated
phosphorylation in regulating the post-endocytic trafficking of a G
protein-coupled receptor.Dopamine receptors
(DARs)3 are members of
the GPCR superfamily and consist of five structurally distinct subtypes
(1,
2). These can be divided into
two subfamilies on the basis of their structure and pharmacological and
transductional properties (3).
The “D1-like” subfamily includes the D1 and
D5 receptors, which couple to the heterotrimeric G proteins
GS or GOLF to stimulate adenylyl cyclase activity and
raise intracellular levels of cAMP. The D2-like subfamily includes
the D2, D3, and D4 receptors, which couple to
inhibitory Gi/o proteins to reduce adenylyl cyclase activity as
well as modulate voltage-gated K+ or Ca2+ channels.
Within the central nervous system, these receptors modulate movement, learning
and memory, reward and addiction, cognition, and certain neurendocrine
functions. As with other GPCRs, the DARs are subject to a wide variety of
regulatory mechanisms, which can either positively or negatively modulate
their expression and functional activity
(4).Upon agonist activation, most GPCRs undergo desensitization, a homeostatic
process that results in a waning of receptor response despite continued
agonist stimulation (5,
6). Desensitization is believed
to involve the phosphorylation of receptors by either G protein-coupled
receptor kinases (GRKs) and/or second messenger-activated kinases such as PKA
or PKC. Homologous forms of desensitization involve only agonist-activated
receptors and appear to be primarily mediated by GRKs. In many cases,
GRK-mediated phosphorylation has been shown to decrease receptor/G protein
interactions and also initiate arrestin binding, which further promotes
endocytosis of the receptor through clathrin-coated pits
(7–9).
Once internalized, GPCRs can engage additional signaling pathways
(10), be sorted for recycling
to the plasma membrane, or targeted for degradation
(7–9).
Among the DARs, the D2 receptor is arguably one of the most
validated drug targets in neurology and psychiatry. For instance, all
receptor-based anti-parkinsonian drugs work via stimulating the D2
DAR (11), whereas all Food and
Drug Administration-approved antipsychotic agents are antagonists of this
receptor subtype (12,
13). The D2 DAR is
also therapeutically targeted in other disorders such as restless legs
syndrome, tardive dyskinesia, Tourette syndrome, and hyperprolactinemia. As
such, more knowledge concerning the regulation of the D2 DAR could
be helpful in improving current therapies or devising new treatment
strategies.In comparison with other GPCRs, however, detailed mechanistic information
concerning regulation of the D2 DAR is mostly lacking, although
some progress has recently been made. For instance, we
(14) and others
(15) have found that
PKC-mediated phosphorylation can regulate both D2 receptor
desensitization and trafficking. In our PKC study, we mapped out all of the
PKC phosphorylation sites within the third intracellular loop (IC3) of the
receptor, and we determined the existence of two PKC phosphorylation domains.
Both of these domains were found to regulate receptor sequestration, whereas
only one domain regulated functional uncoupling in response to PKC activation
(14). In response to agonist
activation, the D2 DAR has also been shown to undergo functional
desensitization (4), although
this has not been intensively investigated. More thoroughly examined is the
observation that agonist stimulation of the D2 DAR promotes its
sequestration from the cell surface into vesicular compartments that appear
distinct from those harboring internalized D1 DARs or
β-adrenergic receptors
(16–21).
In addition to uncertainty over the endocytic pathway involved, controversy
also exists as to whether or not D2 DAR internalization is
dynamin-dependent and whether the internalized receptors can partially or
completely recycle to the cell surface or, alternatively, if they undergo
degradation (19,
21–24).
The D2 DAR does appear to undergo GRK-mediated phosphorylation upon
agonist activation, which has been suggested to promote arrestin association
and receptor sequestration
(16,
19,
25), although this process has
not been studied in detail and its relationship to functional
receptor desensitization is unknown.In this study, we have further characterized GRK-mediated phosphorylation
of the D2 DAR and determined its role in agonist-induced receptor
desensitization, internalization, and recycling. Using site-directed
mutagenesis, we have mapped out all of the GRK phosphorylation sites within
the D2 DAR and determined that these are distinct from the PKC
phosphorylation sites. Using a GRK phosphorylation-null mutant receptor, we
found, surprisingly, that GRK-mediated phosphorylation is not actually
required for agonist-induced receptor desensitization, arrestin association,
or internalization. In contrast, we found that the GRK phosphorylation-null
receptor was impaired in its ability to recycle to the cell surface subsequent
to internalization and was degraded to a greater extent in comparison with the
wild-type receptor. These results suggest that GRK-mediated phosphorylation of
the D2 DAR regulates its intracellular trafficking or sorting once
internalized, a novel mechanism for GRK-mediated regulation of GPCR
function. 相似文献
338.
The novel flavin-dependent thymidylate synthase, ThyX, is absent in humans but several pathogenic bacteria depend exclusively on ThyX activity to synthesize thymidylate. Reduction of the enzyme-bound FAD by NADPH is suggested to be the critical first step in ThyX catalysis. We soaked Mycobacterium tuberculosis ThyX-FAD-BrdUMP ternary complex crystals in a solution containing NADP+ to gain structural insights into the reductive step of the catalytic cycle. Surprisingly, the NADP+ displaced both FAD and BrdUMP from the active site. In the resultant ThyX-NADP+ binary complex, the AMP moiety is bound in a deep pocket similar to that of the same moiety of FAD in the ternary complex, while the nicotinamide part of NADP+ is engaged in a limited number of contacts with ThyX. The additional 2'-phosphate group attached to the AMP ribose of NADP+ could be accommodated with minor rearrangement of water molecules. The newly introduced 2'-phosphate groups are engaged in water-mediated interactions across the non-crystallographic 2-fold axis of the ThyX tetramer, suggesting possibilities for design of high-affinity bivalent inhibitors of this intriguing enzyme. 相似文献
339.
The interplay between religion, morality, and community-making is a core theme across human experience, yet scholars have only recently begun to quantify these links. Drawing on a sample of 1512 self-identified religious – mainly Christian (86.0%) – New Zealanders, we used structural equation modeling to test hypothesized associations between Religious Orientations (Quest, Intrinsic, Extrinsic Personal, Extrinsic Social) and Moral Foundations (Care/Harm, Fairness/Cheating, Loyalty/Betrayal, Authority/Subversion, Sanctity/Degradation). Our results show, for the first time in a comprehensive model, how different ways of valuing communities are associated with different ways of valuing religion. 相似文献
340.
Nzila AM Mberu EK Nduati E Ross A Watkins WM Sibley CH 《International journal for parasitology》2002,32(12):1469-1476
The genotypes of merozoite surface protein-1, merozoite surface protein-2 and glutamine rich protein are frequently used to distinguish recrudescence from reinfection when parasitaemia reappears after antimalarial drug treatment. However, none of the previous reports has clearly assessed the change of genetic diversity following drug treatment. In the present study, we have assessed the impact of pyrimethamine/sulfadoxine and chlorproguanil/dapsone on the genetic diversity of isolates and the multiplicity of infection in patient isolates from Kilifi, Kenya. We have analysed the length polymorphism of merozoite surface protein-1, merozoite surface protein-2 and glutamine rich protein and the data clearly show that treatment with pyrimethamine/sulfadoxine and chlorproguanil/dapsone did not change the multiplicity of infection found in patients, in contrast to the selection that these drugs exert on the genes encoded by the target enzymes. In addition, we report that children of less than 2 years tend to have fewer numbers of clones per isolate when compared with older children. Overall, this study shows that the selection for genes that confer drug resistance is not a factor in reducing the genetic diversity of parasite clones in a patient. 相似文献