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71.
Phillips JJ Javadi Y Millership C Main ER 《Protein science : a publication of the Protein Society》2012,21(3):327-338
Tetratricopeptide repeats (TPRs) are a class of all alpha-helical repeat proteins that are comprised of 34-aa helix-turn-helix motifs. These stack together to form nonglobular structures that are stabilized by short-range interactions from residues close in primary sequence. Unlike globular proteins, they have few, if any, long-range nonlocal stabilizing interactions. Several studies on designed TPR proteins have shown that this modular structure is reflected in their folding, that is, modular multistate folding is observed as opposed to two-state folding. Here we show that TPR multistate folding can be suppressed to approximate two-state folding through modulation of intrinsic stability or extrinsic environmental variables. This modulation was investigated by comparing the thermodynamic unfolding under differing buffer regimes of two distinct series of consensus-designed TPR proteins, which possess different intrinsic stabilities. A total of nine proteins of differing sizes and differing consensus TPR motifs were each thermally and chemically denatured and their unfolding monitored using differential scanning calorimetry (DSC) and CD/fluorescence, respectively. Analyses of both the DSC and chemical denaturation data show that reducing the total stability of each protein and repeat units leads to observable two-state unfolding. These data highlight the intimate link between global and intrinsic repeat stability that governs whether folding proceeds by an observably two-state mechanism, or whether partial unfolding yields stable intermediate structures which retain sufficient stability to be populated at equilibrium. 相似文献
72.
73.
Matthieu Gaudet Nina Remtulla Sophie E Jackson Ewan R G Main Daniel G Bracewell Gabriel Aeppli Paul A Dalby 《Protein science : a publication of the Protein Society》2010,19(8):1544-1554
Protein stability and ligand‐binding affinity measurements are widely required for the formulation of biopharmaceutical proteins, protein engineering and drug screening within life science research. Current techniques either consume too much of often precious biological or compound materials, in large sample volumes, or alternatively require chemical labeling with fluorescent tags to achieve measurements at submicrolitre volumes with less sample. Here we present a quantitative and accurate method for the determination of protein stability and the affinity for small molecules, at only 1.5–20 nL optical sample volumes without the need for fluorescent labeling, and that takes advantage of the intrinsic tryptophan fluorescence of most proteins. Coupled to appropriate microfluidic sample preparation methods, the sample requirements could thus be reduced 85,000‐fold to just 108 molecules. The stability of wild‐type FKBP‐12 and a destabilizing binding‐pocket mutant are studied in the presence and absence of rapamycin, to demonstrate the potential of the technique to both drug screening and protein engineering. The results show that 75% of the interaction energy between FKBP‐12 and rapamycin originates from residue Phe99 in the binding site. 相似文献
74.
This study examined ontogenetic patterns of limb loading, bone strains, and relative changes in bone geometry to explore the relationship between in vivo mechanics and size-related changes in the limb skeleton of two vertebrate taxa. Despite maintaining similar relative limb loads during ontogeny, bone strain magnitudes in the goat radius and emu tibiotarsus generally increased. However, while the strain increases in the emu tibiotarsus were mostly insignificant, strains within the radii of adult goats were two to four times greater than in young goats. The disparity between ontogenetic strain increases in these taxa resulted from differences in ontogenetic scaling patterns of the cross-sectional bone geometry. While the cross-sectional and second moments of area scaled with negative allometry in the goat radius, these measures were not significantly different from isometry in the emu tibiotarsus. Although the juveniles of both taxa exhibited lower strains and higher safety factors than the adults, the radii of the young goats were more robust relative to the adult goats than were the tibiotarsi of the young compared with adult emu. Differences in ontogenetic growth and strain patterns in the limb bones examined likely result from different threat avoidance strategies and selection pressures in the juveniles of these two taxa. 相似文献
75.
Edwards BM Barash SC Main SH Choi GH Minter R Ullrich S Williams E Du Fou L Wilton J Albert VR Ruben SM Vaughan TJ 《Journal of molecular biology》2003,334(1):103-118
It is well established that the humoral immune response can generate antibodies to many different antigens. The antibody diversity required to achieve this is believed to be substantial. However, the extent to which the immune repertoire can generate structural diversity against a single target antigen has never been addressed. Here, we have used phage display to demonstrate the extraordinary capacity of the human antibody repertoire. Over 1000 antibodies, all different in amino acid sequence, were generated to a single protein, B-lymphocyte stimulator (BLyS™ protein). This is a highly diverse panel of antibodies as exemplified by the extensive heavy and light chain germline usage: 42/49 functional heavy chain germlines and 19/33 Vλ and 13/35 Vκ light chain germlines were all represented in the panel of antibodies. Moreover, a high level of sequence diversity was observed in the VH CDR3 domains of these antibodies, with 568 different amino acid sequences identified. Thus we have demonstrated that specific recognition of a single antigen can be achieved from many different VDJ combinations, illustrating the remarkable problem-solving ability of the human immune repertoire. When studied in a biochemical assay, around 500 (40%) of these antibodies inhibited the binding of BLyS to its receptors on B-cell lines. The most potent antibodies inhibited BLyS binding with sub-nanomolar IC50 values and with sub-nanomolar affinities. Such antibodies provide excellent choices as candidates for the treatment of BLyS-associated autoimmune diseases. 相似文献
76.
Mohammad Main Uddin Ammar Abdul Aziz Catherine E. Lovelock 《Global Change Biology》2023,29(12):3331-3346
Mangroves have been identified as blue carbon ecosystems that are natural carbon sinks. In Bangladesh, the establishment of mangrove plantations for coastal protection has occurred since the 1960s, but the plantations may also be a sustainable pathway to enhance carbon sequestration, which can help Bangladesh meet its greenhouse gas (GHG) emission reduction targets, contributing to climate change mitigation. As a part of its Nationally Determined Contribution (NDC) under the Paris Agreement 2016, Bangladesh is committed to limiting the GHG emissions through the expansion of mangrove plantations, but the level of carbon removal that could be achieved through the establishment of plantations has not yet been estimated. The mean ecosystem carbon stock of 5–42 years aged (average age: 25.5 years) mangrove plantations was 190.1 (±30.3) Mg C ha−1, with ecosystem carbon stocks varying regionally. The biomass carbon stock was 60.3 (±5.6) Mg C ha−1 and the soil carbon stock was 129.8 (±24.8) Mg C ha−1 in the top 1 m of which 43.9 Mg C ha−1 was added to the soil after plantation establishment. Plantations at age 5 to 42 years achieved 52% of the mean ecosystem carbon stock calculated for the reference site (Sundarbans natural mangroves). Since 1966, the 28,000 ha of established plantations to the east of the Sundarbans have accumulated approximately 76,607 Mg C year−1 sequestration in biomass and 37,542 Mg C year−1 sequestration in soils, totaling 114,149 Mg C year−1. Continuation of the current plantation success rate would sequester an additional 664,850 Mg C by 2030, which is 4.4% of Bangladesh's 2030 GHG reduction target from all sectors described in its NDC, however, plantations for climate change mitigation would be most effective 20 years after establishment. Higher levels of investment in mangrove plantations and higher plantation establishment success could contribute up to 2,098,093 Mg C to blue carbon sequestration and climate change mitigation in Bangladesh by 2030. 相似文献
77.
BY ALEXANDER H. PURCELL JEAN RICHARDSON ALLAN FINLAY 《The Annals of applied biology》1981,99(3):283-289
The relative titre of the causal agent of X-disease of stone fruits in the non-vector leafhopper Macrosteles fascifrons was tested by injecting dilutions of M. fascifrons extracts into non-infective Colladonus montanus leafhopper vectors. The recipient C. montanus were fed on celery test plants which were then observed for X-disease symptoms. M. fascifrons were assayed at various intervals for up to 37 days after they were fed on X-diseased celery or injected with infectious extracts of the X-agent. Infectivity was detected in M. fascifrons only after 25 or 37 days in separate trials. Whole body extracts but not extracts from detached heads of M. fascifrons that had fed on X-diseased celery were infectious, whereas extracts prepared from the heads of M. fascifrons previously injected with X-agent extracts were infectious. This infectivity was retained for up to four serial passages in M. fascifrons. Electron microscopy of M. fascifrons that had been injected with extracts of the X-disease agent revealed mycoplasma-like organisms (MLO) only intercellularly and appressed to various organs in the haemocoele. No MLO were observed in uninjected M. fascifrons or those injected with extracts from non-infectious C. montanus. These results suggest that, despite multiplication of the X-agent in vivo. barriers in the gut and salivary glands prevent its transmission to plants by M. fascifrons. 相似文献
78.
BY N. WILDING 《The Annals of applied biology》1981,99(1):11-23
During two warm, dry seasons (1975 and 1976) aphid-pathogenic species of Entomophthoraceae introduced into Aphis fabae populations on field beans established briefly but failed to spread. In cool moist seasons (1977 and 1978), the fungi, principally Erynia neoaphidis and Neozygites fresenii, spread more rapidly in treated than untreated plots. In 1977, the maximum aphid population in plots treated with fungi reached a mean of 9000/plant on 19 July compared with 16 000/plant 1 wk later in untreated plots. The corresponding yield of beans in treated plots was twice that in untreated plots though only half that in plots kept free of aphids with pirimicarb. In two experiments in 1978, the maximum aphid population in treated areas was 700/plant, half that in untreated areas and 1 to 2 wk earlier. Yields from treated plots, however, were not significantly different from those from untreated plots. In nature, the fungi attack A. fabae populations in England only after they have become damaging, partly because fungal inoculum is sparse when the aphid population is small. 相似文献
79.
The structure of the transition state for folding/unfolding of the immunophilin FKBP12 has been characterised using a combination of protein engineering techniques, unfolding kinetics, and molecular dynamics simulations. A total of 34 mutations were made at sites throughout the protein to probe the extent of secondary and tertiary structure in the transition state. The transition state for folding is compact compared with the unfolded state, with an approximately 30 % increase in the native solvent-accessible surface area. All of the interactions are substantially weaker in the transition state, as probed by both experiment and molecular dynamics simulations. In contrast to some other proteins of this size, no element of structure is fully formed in the transition state; instead, the transition state is similar to that found for smaller, single-domain proteins, such as chymotrypsin inhibitor 2 and the SH3 domain from alpha-spectrin. For FKBP12, the central three strands of the beta-sheet, beta-strand 2, beta-strand 4 and beta-strand 5, comprise the most structured region of the transition state. In particular Val101, which is one of the most highly buried residues and located in the middle of the central beta-strand, makes approximately 60 % of its native interactions. The outer beta-strands and the ends of the central beta-strands are formed to a lesser degree. The short alpha-helix is largely unstructured in the transition state, as are the loops. The data are consistent with a nucleation-condensation model of folding, the nucleus of which is formed by side-chains within beta-strands 2, 4 and 5, and the C terminus of the alpha-helix. The precise residues involved in the nucleus differ in the two simulated transition state ensembles, but the interacting regions of the protein are conserved. These residues are distant in the primary sequence, demonstrating the importance of tertiary interactions in the transition state. The two independently derived transition state ensembles are structurally similar, which is consistent with a Bronsted analysis confirming that the transition state is an ensemble of states close in structure. 相似文献
80.
Stomach contents were identified from 206 Antarctic starry skate (Amblyraja georgiana) that were collected during three groundfish surveys (September 2007, April 2008 and January 2009) at South Georgia, Southern
Ocean. The diet of A. georgiana varied with skate size and between years. Preferred prey included fish (particularly for larger individuals) and Antarctic
krill, Euphausia superba, as well as amphipods, polychaetes and other benthic fauna. The skate A. georgiana appears to be an opportunistic predator, and the clear presence of Antarctic krill in this demersal predator’s diet may indicate
a benthic habit of this euphausiid species, which has hitherto mainly been considered as occupying a purely pelagic niche. 相似文献