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41.
Catherine E. Jessop Timothy J. Tavender Rachel H. Watkins Joseph E. Chambers Neil J. Bulleid 《The Journal of biological chemistry》2009,284(4):2194-2202
The formation of disulfides within proteins entering the secretory pathway
is catalyzed by the protein disulfide isomerase family of endoplasmic
reticulum localized oxidoreductases. One such enzyme, ERp57, is thought to
catalyze the isomerization of non-native disulfide bonds formed in
glycoproteins with unstructured disulfide-rich domains. Here we investigated
the mechanism underlying ERp57 specificity toward glycoprotein substrates and
the interdependence of ERp57 and the calnexin cycle for their correct folding.
Our results clearly show that ERp57 must be physically associated with the
calnexin cycle to catalyze isomerization reactions with most of its
substrates. In addition, some glycoproteins only require ERp57 for correct
disulfide formation if they enter the calnexin cycle. Hence, the specificity
of ER oxidoreductases is not only determined by the physical association of
enzyme and substrate but also by accessory factors, such as calnexin and
calreticulin in the case of ERp57. These conclusions suggest that the calnexin
cycle has evolved with a specialized oxidoreductase to facilitate native
disulfide formation in complex glycoproteins.The ability to form disulfide bonds within proteins entering the secretory
pathway is essential for cell survival and occurs within the endoplasmic
reticulum (ER).3 For
proteins with few disulfides, the process can be catalyzed by oxidation of
cysteine residues to form the correct, native disulfide; however, for proteins
with several disulfides, an isomerization reaction is also required to correct
non-native disulfides formed following oxidation
(1). Both these reactions are
catalyzed by a group of ER-resident proteins that belong to the protein
disulfide isomerase (PDI) family, which comprises over 17 members
(2). It is well established
that PDI and several other family members are able to catalyze the formation
and isomerization of disulfides in vitro, although the exact function
of each of the family members in vivo is unknown. It is still an open
question as to whether they all catalyze similar reactions and have distinct
substrate specificities or whether they have distinct enzymatic functions
related to the breaking and formation of disulfides.For one member of the PDI family, the function and substrate specificity is
a little clearer. ERp57 has been shown previously to interact specifically
with glycoproteins during their folding
(3). The enzyme is physically
associated with either calnexin or calreticulin
(4) and is therefore ideally
placed to catalyze correct disulfide formation within proteins entering the
calnexin/calreticulin cycle (referred to subsequently just as the calnexin
cycle). In addition, the ability of ERp57 to catalyze the refolding of
substrates in vitro is greatly enhanced if the substrate is bound to
calnexin (5). Recently,
substrates for the reduction or isomerization reaction catalyzed by ERp57 have
been identified by trapping mixed disulfides between enzyme and substrate
(6). Strikingly, there was an
overrepresentation of substrate proteins with cysteine-rich domains containing
little secondary structure, suggesting that the main function of ERp57 is in
the isomerization of non-native disulfides. ERp57 has also been shown to
function independently from the calnexin cycle. It is a component of the MHC
class I loading complex where it forms a disulfide-linked complex with tapasin
and is thought to either stabilize the complex or facilitate correct assembly
of class I molecules (7,
8). Recently, ERp57 has been
demonstrated to isomerize interchain disulfides in the major capsid protein,
VP1, of simian virus 40 (9).
The ability to dissociate VP1 pentamers by ERp57 does not require the
substrate to interact with the calnexin cycle. Hence, it is still unclear how
ERp57 recognizes its substrates, and in particular, whether this recognition
is solely determined by an interaction with the calnexin cycle.The recognition of substrates by PDI is somewhat clearer in that one
particular domain within the protein (the b′ domain) has been shown to
be primarily responsible for substrate recognition and peptide binding
(10). The corresponding domain
within ERp57 has been shown to be responsible for interaction with the
calnexin cycle (11),
suggesting that for ERp57, substrate recognition must occur outside this
domain or is determined solely by substrate interaction with calnexin via its
oligosaccharide side chain. Hence, the aim of our study was to evaluate the
necessity of the calnexin cycle both for ERp57 to recognize its substrates and
for correct folding of glycoproteins. ERp57 was found to be required for the
efficient folding of one substrate, influenza virus hemagglutinin (HA), but
only when it entered the calnexin cycle. HA did not require ERp57 to fold if
it was blocked from entering the calnexin cycle. In contrast, β1-integrin
does not fold efficiently either if ERp57 was depleted or if ERp57 is blocked
from entering the calnexin cycle
(6). Although ERp57 may be
dispensable for the folding of some glycoproteins, the interaction with
calnexin commits them to an ERp57-dependent fate. We also found that the
majority of ERp57 substrates need to enter the calnexin cycle to be acted upon
by the enzyme, demonstrating that substrate specificity is primarily dependent
upon substrate entry into the calnexin cycle. 相似文献
42.
While the hypothalamo-pituitary-adrenocortical (HPA) response to stress appears to be conserved in vertebrates, the manner in which it is activated and its actions vary. We examine two trends in the stress biology literature that have been addressed in amphibian and reptilian species: (1). variable interactions among stress, corticosterone, and reproduction and (2). adrenocortical modulation. In the first topic we examine context-dependent interactions among stress, corticosterone, and reproduction. An increasing number of studies report positive associations between reproduction and corticosterone that contradict the generalization that stress inhibits reproduction. Moderately elevated levels of stress hormones appear to facilitate reproduction by mobilizing energy stores. In contrast, pronounced activation of the HPA axis and extremely elevated levels of stress hormones appear to inhibit reproduction. Much of these contrasting effects of stress and reproduction can be explained by expanding the Energetics-Hormone Vocalization Model, proposed for anuran calling behavior, to other taxa. In the second topic, a number of amphibians and reptiles modulate their HPA stress response. Adrenocortical modulation can occur at multiple levels and due to a variety of factors. However, we have little information as to the physiological basis for the variability. We suggest that several ecologically based ideas, such as variability in the length of the breeding season and lifetime reproductive opportunities, can be used to explain the utility of adrenocortical modulation in these taxa. 相似文献
43.
Plasticity or evolution in behavioural responses are key attributes of successful animal invasions. In northern Australia, the invasive cane toad (Rhinella marina) recently invaded semi-arid regions. Here, cane toads endure repeated daily bouts of severe desiccation and thermal stress during the long dry season (April–October). We investigated whether cane toads have shifted their ancestral nocturnal rehydration behaviour to one that exploits water resources during the day. Such a shift in hydration behaviour could increase the fitness of individual toads by reducing exposure to desiccation and thermal stress suffered during the day even within terrestrial shelters. We used a novel method (acoustic tags) to monitor the daily hydration behaviour of 20 toads at two artificial reservoirs on Camfield station, Northern Territory. Remarkably, cane toads visited reservoirs to rehydrate during daylight hours, with peaks in activity between 9.00 and 17.00. This diurnal pattern of rehydration activity contrasts with nocturnal rehydration behaviour exhibited by adult toads in their native geographical range and more mesic parts of Australia. Our results demonstrate that cane toads phase shift a key behaviour to survive in a harsh semi-arid landscape. Behavioural phase shifts have rarely been reported in invasive species but could facilitate ongoing invasion success. 相似文献
44.
Limited effect of anthropogenic habitat fragmentation on molecular diversity in a rain forest skink, Gnypetoscincus queenslandiae 总被引:3,自引:0,他引:3
To examine the effects of recent habitat fragmentation, we assayed genetic diversity in a rain forest endemic lizard, the prickly forest skink (Gnypetoscincus queenslandiae), from seven forest fragments and five sites in continuous forest on the Atherton tableland of northeastern Queensland, Australia. The rain forest in this region was fragmented by logging and clearing for dairy farms in the early 1900s and most forest fragments studied have been isolated for 50-80 years or nine to 12 skink generations. We genotyped 411 individuals at nine microsatellite DNA loci and found fewer alleles per locus in prickly forest skinks from small rain forest fragments and a lower ratio of allele number to allele size range in forest fragments than in continuous forest, indicative of a decrease in effective population size. In contrast, and as expected for populations with small neighbourhood sizes, neither heterozygosity nor variance in allele size differed between fragments and sites in continuous forests. Considering measures of among population differentiation, there was no increase in FST among fragments and a significant isolation by distance pattern was identified across all 12 sites. However, the relationship between genetic (FST) and geographical distance was significantly stronger for continuous forest sites than for fragments, consistent with disruption of gene flow among the latter. The observed changes in genetic diversity within and among populations are small, but in the direction predicted by the theory of genetic erosion in recently fragmented populations. The results also illustrate the inherent difficulty in detecting genetic consequences of recent habitat fragmentation, even in genetically variable species, and especially when effective population size and dispersal rates are low. 相似文献
45.
Jessop TS Sumner JM Limpus CJ Whittier JM 《Comparative biochemistry and physiology. Part A, Molecular & integrative physiology》2004,137(1):197-204
We investigated plasma hormone profiles of corticosterone and testosterone in immature hawksbill turtles (Eretmochelys imbricata) in response to a capture stress protocol. Further, we examined whether sex and body condition were covariates associated with variation in the adrenocortical response of immature turtles. Hawksbill turtles responded to the capture stress protocol by significantly increasing plasma levels of corticosterone over a 5 h period. There was no significant sex difference in the corticosterone stress response of immature turtles. Plasma testosterone profiles, while significantly different between the sexes, did not exhibit a significant change during the 5 h capture stress protocol. An index of body condition was not significantly associated with a turtle's capacity to produce plasma corticosterone both prior to and during exposure to the capture stress protocol. In summary, while immature hawksbill turtles exhibited an adrenocortical response to a capture stress protocol, neither their sex nor body condition was responsible for variation in endocrine responses. This lack of interaction between the adrenocortical response and these internal factors suggests that the inactive reproductive- and the current energetic- status of these immature turtles are important factors that could influence plasma hormone profiles during stress. 相似文献
46.
Goedkoop AY Kraan MC Picavet DI de Rie MA Teunissen MB Bos JD Tak PP 《Arthritis research & therapy》2004,6(4):R326-R334
Psoriasis and psoriatic arthritis are inflammatory diseases that respond well to anti-tumour necrosis factor-α therapy. To
evaluate the effects of anti-tumour necrosis factor-α treatment on expression of adhesion molecules and angiogenesis in psoriatic
lesional skin and synovial tissue, we performed a prospective single-centre study with infliximab therapy combined with stable
methotrexate therapy. Eleven patients with both active psoriasis and psoriatic arthritis received infusions of infliximab
(3 mg/kg) at baseline, and at weeks 2, 6, 14 and 22 in an open-label study. In addition, patients continued to receive stable
methotrexate therapy in dosages ranging from 5 to 20 mg/week. Clinical assessments, including Psoriasis Area and Severity
Index (PASI) and Disease Activity Score (DAS), were performed at baseline and every 2 weeks afterward. In addition, skin biopsies
from a target psoriatic plaque and synovial tissue biopsies from a target joint were taken before treatment and at week 4.
Immunohistochemical analysis was performed to detect the number of blood vessels, the expression of adhesion molecules and
the presence of vascular growth factors. Stained sections were evaluated by digital image analysis. At week 16, the mean PASI
was reduced from 12.3 ± 2.4 at baseline to 1.8 ± 0.4 (P ≤ 0.02). The mean DAS was reduced from 6.0 ± 0.5 to 3.6 ± 0.6 (P ≤ 0.02). We found some fluctuations in DAS response as compared with the change in PASI, with the latter exhibiting a steady
decrease over time. After 4 weeks the cell infiltrate was reduced in both skin and synovium. There was a significant reduction
in the number of blood vessels in dermis and synovium at week 4. A significant reduction in the expression of αvβ3 integrin, a marker of neovascularization, was also found in both skin and synovium at week 4. In addition, a significant
reduction in the expression of adhesion molecules was observed in both skin and synovium at week 4. We also observed a trend
toward reduced expression of vascular endothelial growth factor in both skin and synovium. In conclusion, low-dose infliximab
treatment leads to decreased neoangiogenesis and deactivation of the endothelium, resulting in decreased cell infiltration
and clinical improvement in psoriasis and psoriatic arthritis. 相似文献
47.
In nature, green turtles (Chelonia mydas) can exhibit nocturnal activity in addition to their typically diurnal activity cycle. We examined whether nocturnal activity in captive and free-living green turtles altered daily plasma profiles of melatonin (MEL) and corticosterone (CORT). In captivity, diurnally active green turtles expressed distinct diel cycles in MEL and CORT; a nocturnal rise was observed in MEL and a diurnal rise was observed in CORT. However, when induced to perform both low- and high-intensity nocturnal activity, captive green turtles exhibited a significant decrease in MEL, compared to inactive controls. In contrast, plasma CORT increased significantly with nocturnal activity, and further, the relative increase in CORT was correlated with the intensity of the nocturnal behavior. In free-living green turtles that performed nocturnal activity including: nesting, mate searching, and feeding/swimming behaviors, plasma profiles in MEL and CORT exhibited relatively little, or no, daily fluctuation. Our findings demonstrate that nocturnal activity in green turtles is often associated with MEL and CORT profiles that resemble those measured during the day. We speculate that these conspicuous changes in MEL and CORT during nocturnal activity could either support or promote behaviors that enable acquisition of transient resources important to the survival and reproductive success of green turtles. 相似文献
48.
Summary In E. coli K-12 the argF gene is flanked by ISI sequences in direct repeat. Mutants that overproduce the argF-coded enzyme ornithine transcarbamylase can be selected; we have shown that in one class of these mutants there is an approximately forty five-fold amplification of the region bounded by the ISI repeats. This class of mutants has been detected only in strains in which the F-factor is integrated in cis to the region. 相似文献
49.
50.
Summary The effect of waterlogging on water use and nutrient uptake in sunflower and sorghum was investigated in relation to stage of development of the crops and the timing and duration of waterlogging. Waterlogging at the vegetative and floral initiation stages of plant growth induced a reduction in water use of sunflower, with corresponding declines in leaf expansion and leaf water potential; in sorghum, the transpiration rates were much lower than for sunflower and relatively unaffected by waterlogging. Waterlogging at anthesis, however, caused an immediate reduction in water use in sunflower with a similar but delayed effect in sorghum. The differences in response of these two species are discussed in relation to the relative importance of water stress and nutrient uptake. Plant analysis at maturity indicated that waterlogging at any growth stage reduced both total and seed phosphorus in sunflower; similar effects were recorded with sorghum, with the exception of anthesis waterlogging which did not reduce nutrient uptake. Waterlogging effects on plant potassium levels were variable. 相似文献