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51.
Po-Chao Wen Brandy Verhalen Stephan Wilkens Hassane S. Mchaourab Emad Tajkhorshid 《The Journal of biological chemistry》2013,288(26):19211-19220
P-glycoprotein (Pgp) is one of the most biomedically relevant transporters in the ATP binding
cassette (ABC) superfamily due to its involvement in developing multidrug resistance in cancer
cells. Employing molecular dynamics simulations and double electron-electron resonance spectroscopy,
we have investigated the structural dynamics of membrane-bound Pgp in the inward-facing state and
found that Pgp adopts an unexpectedly wide range of conformations, highlighted by the degree of
separation between the two nucleotide-binding domains (NBDs). The distance between the two NBDs in
the equilibrium simulations covers a range of at least 20 Å, including, both, more open and
more closed NBD configurations than the crystal structure. The double electron-electron resonance
measurements on spin-labeled Pgp mutants also show wide distributions covering both longer and
shorter distances than those observed in the crystal structure. Based on structural and sequence
analyses, we propose that the transmembrane domains of Pgp might be more flexible than other
structurally known ABC exporters. The structural flexibility of Pgp demonstrated here is not only in
close agreement with, but also helps rationalize, the reported high NBD fluctuations in several ABC
exporters and possibly represents a fundamental difference in the transport mechanism between ABC
exporters and ABC importers. In addition, during the simulations we have captured partial entrance
of a lipid molecule from the bilayer into the lumen of Pgp, reaching the putative drug binding site.
The location of the protruding lipid suggests a putative pathway for direct drug recruitment from
the membrane. 相似文献
52.
Brandy L. Akin Thomas D. Hurley Zhenhui Chen Larry R. Jones 《The Journal of biological chemistry》2013,288(42):30181-30191
P-type ATPases are a large family of enzymes that actively transport ions across biological membranes by interconverting between high (E1) and low (E2) ion-affinity states; these transmembrane transporters carry out critical processes in nearly all forms of life. In striated muscle, the archetype P-type ATPase, SERCA (sarco(endo)plasmic reticulum Ca2+-ATPase), pumps contractile-dependent Ca2+ ions into the lumen of sarcoplasmic reticulum, which initiates myocyte relaxation and refills the sarcoplasmic reticulum in preparation for the next contraction. In cardiac muscle, SERCA is regulated by phospholamban (PLB), a small inhibitory phosphoprotein that decreases the Ca2+ affinity of SERCA and attenuates contractile strength. cAMP-dependent phosphorylation of PLB reverses Ca2+-ATPase inhibition with powerful contractile effects. Here we present the long sought crystal structure of the PLB-SERCA complex at 2.8-Å resolution. The structure was solved in the absence of Ca2+ in a novel detergent system employing alkyl mannosides. The structure shows PLB bound to a previously undescribed conformation of SERCA in which the Ca2+ binding sites are collapsed and devoid of divalent cations (E2-PLB). This new structure represents one of the key unsolved conformational states of SERCA and provides a structural explanation for how dephosphorylated PLB decreases Ca2+ affinity and depresses cardiac contractility. 相似文献
53.
Brandy M. Toner Ryan A. Lesniewski Jeffrey J. Marlow Lindsey J. Briscoe Cara M. Santelli Wolfgang Bach 《Geomicrobiology journal》2013,30(4):313-326
Mid-ocean ridge hydrothermal venting creates sulfide deposits containing gradients in mineralogy, fluid chemistry, and temperature. Even when hydrothermal circulation ceases, sulfides are known to host microbial communities. The relationship between mineralogy and microbial community composition in low-temperature, rock-hosted systems has not been resolved at any spatial scale, local or global. To examine the hypothesis that geochemistry of seafloor deposits is a dominant parameter driving environmental pressure for bacterial communities at low-temperature, the shared community membership, richness, and structure was measured using 16S rRNA gene sequences. The focus of the study was on hydrothermally inactive seafloor deposits from multiple locations within one deposit (e.g., single extinct chimney), within one vent field (intra-vent field), and among globally distributed vent fields from three ocean basins (inter-vent field). Distinct mineral substrates, such as hydrothermally inactive sulfides versus basalts, host different communities at low temperature in spite of close geographic proximity and contact with the same hydrothermally influenced deep-sea water. Furthermore, bacterial communities inhabiting hydrothermally inactive sulfide deposits from geographically distant locations cluster together in community cladograms to the exclusion of other deep-sea substrates and settings. From this study, we conclude that at low temperature, mineralogy was a more important variable determining microbial community composition than geographic factors. Supplemental materials are available for this article. Go to the publisher's online edition of Geomicrobiology Journal to view the supplemental file. 相似文献
54.
55.
Houser BL Tilburgs T Hill J Nicotra ML Strominger JL 《Journal of immunology (Baltimore, Md. : 1950)》2011,186(4):2633-2642
Several important events occur at the maternal-fetal interface, including generation of maternal-fetal tolerance, remodeling of the uterine smooth muscle and its spiral arteries and glands, and placental construction. Fetal-derived extravillous trophoblasts come in direct contact with maternal decidual leukocytes. Macrophages represent ~20% of the leukocytes at this interface. In this study, two distinct subsets of CD14(+) decidual macrophages (dMs) are found to be present in first-trimester decidual tissue, CD11c(HI) and CD11c(LO). Gene expression analysis by RNA microarray revealed that 379 probes were differentially expressed between these two populations. Analysis of the two subsets revealed several clusters of coregulated genes that suggest distinct functions for these subsets in tissue remodeling, growth, and development. CD11c(HI) dMs express genes associated with lipid metabolism and inflammation, whereas CD11c(LO) dMs express genes associated with extracellular matrix formation, muscle regulation, and tissue growth. The CD11c(HI) dMs also differ from CD11c(LO) dMs in their ability to process protein Ag and are likely to be the major APCs in the decidua. Moreover, these populations each secrete both proinflammatory and anti-inflammatory cytokines that may contribute to the balance that establishes fetal-maternal tolerance. Thus, they do not fit the conventional M1/M2 categorization. 相似文献
56.
Endonuclease (Endo) III and formamidopyrimidine-N-glycosylase (Fpg) are two of the predominant DNA glycosylases in Escherichia coli that remove oxidative base damage. In cell extracts and purified form, Endo III is generally more active toward oxidized pyrimidines, while Fpg is more active towards oxidized purines. However, the substrate specificities of these enzymes partially overlap in vitro. Less is known about the relative contribution of these enzymes in restoring the genomic template following oxidative damage. In this study, we examined how efficiently Endo III and Fpg repair their oxidative substrates in vivo following treatment with hydrogen peroxide. We found that Fpg was nonredundant and required to rapidly remove its substrate lesions on the chromosome. In addition, Fpg also repaired a significant portion of the lesions recognized by Endo III, suggesting that it plays a prominent role in the global repair of both purine damage and pyrimidine damage in vivo. By comparison, Endo III did not affect the repair rate of Fpg substrates and was only responsible for repairing a subset of its own substrate lesions in vivo. The absence of Endo VIII or nucleotide excision repair did not significantly affect the global repair of either Fpg or Endo III substrates in vivo. Surprisingly, replication recovered after oxidative DNA damage in all mutants examined, even when lesions persisted in the DNA, suggesting the presence of an efficient mechanism to process or overcome oxidative damage encountered during replication. 相似文献
57.
PCK1 and PCK2 as candidate diabetes and obesity genes 总被引:1,自引:0,他引:1
The PCK1 gene (Pck1 in rodents) encodes the cytosolic isozyme of phosphoenolpyruvate carboxykinase (PEPCK-C), which is well-known for its function
as a gluconeogenic enzyme in the liver and kidney. Mouse studies involving whole body and tissue-specific Pck1 knockouts as well as tissue-specific over-expression of PEPCK-C have resulted in type 2 diabetes as well as several surprising
phenotypes including obesity, lipodystrophy, fatty liver, and death. These phenotypes arise from perturbations not only in
gluconeogenesis but in two additional metabolic functions of PEPCK-C: (1) cataplerosis which maintains metabolic flux through
the Krebs cycle by removing excess oxaloacetate, and (2) glyceroneogenesis which produces glycerol-3-phosphate as a precursor
for fatty acid esterification into triglycerides. PEPCK-C catalyzes the conversion of oxaloacetate + GTP to phosphoenolpyruvate + GDP + CO2. It is in part the tissue-specificity of this simple reaction that results in the variety of phenotypes listed above. Briefly:
(1) A 7-fold over-expression of PEPCK-C in the livers of mice causes excessive glucose production. (2) Mice with a whole-body
knockout of Pck1 die within 2–3 days of birth, not from hypoglycemia, but probably because the Krebs cycle slows to approximately 10% of normal
in the absence of cataplerosis. (3) Mice with a liver-specific knockout have an inability to remove oxaloacetate from the
Krebs cycle, which leads to a fatty liver following a fast. (4) An adipose-specific knockout of Pck1 results in a fraction of the mice developing lipodystrophy due to lost glyceroneogenesis and a consequent decrease in fatty
acid re-esterification. (5) Finally, disregulated over-expression of PEPCK-C in adipose tissue increases fatty acid re-esterification
leading to obesity. These varied experimental phenotypes in mice have led us to postulate that abnormal production of PEPCK
isozymes encoded by two PEPCK genes, PCK1 and PCK2, in humans could have similar consequences (Beale, E. G. et al. (2004). Trends in Endocrinology and Metabolism, 15, 129–135). The purpose of this review is to further explore these possibilities. 相似文献
58.
Heidi L. Pecoraro Melissa R. Berg Brandy L. Dozier Lauren Drew Martin Cindy T. McEvoy Michael H. Davies Rebecca Ducore 《Journal of medical primatology》2019,48(3):186-188
Invasive Candida infections (ICI) have been associated with neurodevelopmental impairment or death in human pre‐term neonates. Candidiasis in nonhuman primates is seen mostly in immunosuppressed animals, and ICI is not commonly reported. Here, we report a case of Candida albicans‐associated ICI in a pre‐term neonatal rhesus macaque. 相似文献
59.
A metagenomics‐based approach to the top‐down effect on the detritivore food web: a salamanders influence on fungal communities within a deciduous forest 下载免费PDF全文
Donald M. Walker Brandy R. Lawrence Dakota Esterline Sean P. Graham Michael A. Edelbrock Jessica A. Wooten 《Ecology and evolution》2014,4(21):4106-4116
The flow of energy within an ecosystem can be considered either top‐down, where predators influence consumers, or bottom‐up, where producers influence consumers. Plethodon cinereus (Red‐backed Salamander) is a terrestrial keystone predator who feeds on invertebrates within the ecosystem. We investigated the impact of the removal of P. cinereus on the detritivore food web in an upland deciduous forest in northwest Ohio, U.S.A. A total of eight aluminum enclosures, each containing a single P. cinereus under a small log, were constructed in the deciduous forest. On Day 1 of the experiment, four salamanders were evicted from four of the eight enclosures. Organic matter and soil were collected from the center of each enclosure at Day 1 and Day 21. From each sample, DNA was extracted, fungal‐specific amplification performed, and 454 pyrosequencing was used to sequence the nuclear ribosomal internal transcribed spacer (ITS2) region and partial ribosomal large subunit (LSU). Changes in overall fungal community composition or species diversity were not statistically significant between treatments. Statistically significant shifts in the most abundant taxonomic groups of fungi were documented in presence but not absence enclosures. We concluded that P. cinereus does not affect the overall composition or diversity of fungal communities, but does have an impact on specific groups of fungi. This study used a metagenomics‐based approach to investigate a missing link among a keystone predator, P. cinereus, invertebrates, and fungal communities, all of which are critical in the detritivore food web. 相似文献
60.
Fan JB Chen J April CS Fisher JS Klotzle B Bibikova M Kaper F Ronaghi M Linnarsson S Ota T Chien J Laurent LC Loring JF Nisperos SV Chen GY Zhong JF 《PloS one》2012,7(2):e30794