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811.
The TPR domain of BepA is required for productive interaction with substrate proteins and the β‐barrel assembly machinery complex 下载免费PDF全文
Yasushi Daimon Chigusa Iwama‐Masui Yoshiki Tanaka Takuya Shiota Takehiro Suzuki Ryoji Miyazaki Hiroto Sakurada Trevor Lithgow Naoshi Dohmae Hiroyuki Mori Tomoya Tsukazaki Shin‐ichiro Narita Yoshinori Akiyama 《Molecular microbiology》2017,106(5):760-776
BepA (formerly YfgC) is an Escherichia coli periplasmic protein consisting of an N‐terminal protease domain and a C‐terminal tetratricopeptide repeat (TPR) domain. We have previously shown that BepA is a dual functional protein with chaperone‐like and proteolytic activities involved in membrane assembly and proteolytic quality control of LptD, a major component of the outer membrane lipopolysaccharide translocon. Intriguingly, BepA can associate with the BAM complex: the β‐barrel assembly machinery (BAM) driving integration of β‐barrel proteins into the outer membrane. However, the molecular mechanism of BepA function and its association with the BAM complex remains unclear. Here, we determined the crystal structure of the BepA TPR domain, which revealed the presence of two subdomains formed by four TPR motifs. Systematic site‐directed in vivo photo‐cross‐linking was used to map the protein–protein interactions mediated by the BepA TPR domain, showing that this domain interacts both with a substrate and with the BAM complex. Mutational analysis indicated that these interactions are important for the BepA functions. These results suggest that the TPR domain plays critical roles in BepA functions through interactions both with substrates and with the BAM complex. Our findings provide insights into the mechanism of biogenesis and quality control of the outer membrane. 相似文献
812.
Ayumu Niida Shigekazu Sasaki Kazuko Yonemori Tomoya Sameshima Masahiro Yaguchi Taiji Asami Kotaro Sakamoto Masahiro Kamaura 《Bioorganic & medicinal chemistry letters》2017,27(12):2757-2761
A structure-activity relationship study of a K-Ras(G12D) selective inhibitory cyclic peptide, KRpep-2d was performed. Alanine scanning of KRpep-2d focusing on the cyclic moiety showed that Leu7, Ile9, and Asp12 are the key elements for K-Ras(G12D) selective inhibition of KRpep-2d. The cysteine bridging was also examined to identify the stable analog of KRpep-2d under reductive conditions. As a result, the KRpep-2d analog (12) including mono-methylene bridging showed potent K-Ras(G12D) selective inhibition in both the presence and the absence of dithiothreitol. This means that mono-methylene bridging is an effective strategy to obtain a reduction-resistance analog of parent disulfide cyclic peptides. Peptide 12 inhibited proliferation of K-Ras(G12D)-driven cancer cells significantly. These results gave valuable information for further optimization of KRpep-2d to provide novel anti-cancer drug candidates targeting the K-Ras(G12D) mutant. 相似文献
813.
A series of N-alkyl-, N-hydroxyalkyl-, N-haloalkyl- and N-carboxyalkyl-N-nitrosoureas and some related derivatives were tested for mutagenicity in E. coli B (Arg-) H/r30R (wild-type) and its isogenic Hs30R (uvrA) tester strains. Mutagenic potency in Hs30R, in general, appears to depend on the substituent (-OH, -OCH3, -halogen, -COO- or -COOCH3) on the alkyl group, rather than the chain length or branching of the alkyl group. On the other hand, mutagenic potency in the wild-type H/r30R strain depends on buliness of the substituent and alkyl moiety. The term "uvrA-dependence" of mutation frequency is then defined as the ratio of the mutation frequency in Hs30R versus that in H/r30R at 1 mM dose of mutagens. Its dependence on structure is also discussed. A good correlation was found with the van der Waals volume of the substituted alkyl group, except for compounds having a carboxyalkyl or a branched alkyl group. The carboxyalkyl derivatives are the most weakly mutagenic and most seriously "uvrA-dependent", probably due to the negative charge of the molecule. The possibility of forming epoxides and lactones from N-hydroxyalkyl- and N-carboxyalkyl-N-nitrosoureas, respectively, and their participation in mutagenic potency are discussed. An attempt to correlate the partition property and activation rate of the N-nitrosoureas with mutagenic characteristics proved unsuccessful. 相似文献
814.
815.
A structural characterization of bound water molecules in the cyclic tetrasaccharide, cyclo-{-->6}-alpha-D-Glcp-(1-->3)-alpha-D-Glcp-(1-->6)-alpha-D-Glcp-(1-->3)-alpha-D-Glcp-(1-->), was carried out by NMR spectroscopy. H-1', 2'-OH, H-3', and 4'-OH of the 3-O-glycosylated residue and H-1 of the 6-O-glycosylated residue were found to cross-relax with protons of bound waters using the double-pulsed field-gradient spin-echo ROESY experiment. In the crystal structure, one water molecule is located in the center of the plate, and its temperature factor is very low, indicating that this water molecule is an intrinsic component. 相似文献
816.
Hideki Okada Eri Fukushi Akira Yamamori Naoki Kawazoe Shuichi Onodera Jun Kawabata Norio Shiomi 《Carbohydrate research》2011,(16):2633
Fermented beverage of plant extracts was prepared from the extracts of approximately 50 types of vegetables and fruits. Natural fermentation was carried out mainly by lactic acid bacteria (Leuconostoc spp.) and yeast (Zygosaccharomyces spp. and Pichia spp.). Two oligosaccharides containing an α-fructofuranoside linkage were detected in this beverage and isolated using carbon–Celite column chromatography and preparative HPLC. The structural confirmation of the saccharides was determined by methylation analysis, MALDI-TOF-MS, and NMR measurements. These saccharides were identified as α-d-fructofuranosyl-(2→6)-d-glucopyranose, which was isolated from a natural source for the first time, and a novel saccharide β-d-fructopyranosyl-(2→6)-α-d-fructofuranosyl-(2↔1)-α-d-glucopyranoside. 相似文献
817.
Saito K Enya K Oneyama C Hikita T Okada M 《Biochemical and biophysical research communications》2008,366(4):969-975
To elucidate the regulatory mechanism of cell transformation induced by c-Src tyrosine kinase, we performed a proteomic analysis of tyrosine phosphorylated proteins that interact with c-Src and/or its negative regulator Csk. The c-Src interacting proteins were affinity-purified from Src transformed cells using the Src SH2 domain as a ligand. LC-MS/MS analysis of the purified proteins identified general Src substrates, such as focal adhesion kinase and paxillin, and ZO-1/2 as a transformation-dependent Src target. The Csk binding proteins were analyzed by a tandem affinity purification method. In addition to the previously identified Csk binding proteins, including Cbp/PAG, paxillin, and caveolin-1, we found that ZO-1/2 could also serve as a major Csk binding protein. ZO-2 was phosphorylated concurrently with Src transformation and specifically bound to Csk in a Csk SH2 dependent manner. These results suggest novel roles for ZO proteins as Src/Csk scaffolds potentially involved in the regulation of Src transformation. 相似文献
818.
819.
A cell leakproof porous poly(DL ‐lactic‐co‐glycolic acid) (PLGA)‐collagen hybrid scaffold was prepared by wrapping the surfaces of a collagen sponge except the top surface for cell seeding with a bi‐layered PLGA mesh. The PLGA‐collagen hybrid scaffold had a structure consisting of a central collagen sponge formed inside a bi‐layered PLGA mesh cup. The hybrid scaffold showed high mechanical strength. The cell seeding efficiency was 90.0% when human mesenchymal stem cells (MSCs) were seeded in the hybrid scaffold. The central collagen sponge provided enough space for cell loading and supported cell adhesion, while the bi‐layered PLGA mesh cup protected against cell leakage and provided high mechanical strength for the collagen sponge to maintain its shape during cell culture. The MSCs in the hybrid scaffolds showed round cell morphology after 4 weeks culture in chondrogenic induction medium. Immunostaining demonstrated that type II collagen and cartilaginous proteoglycan were detected in the extracellular matrices. Gene expression analyses by real‐time PCR showed that the genes encoding type II collagen, aggrecan, and SOX9 were upregulated. These results indicated that the MSCs differentiated and formed cartilage‐like tissue when being cultured in the cell leakproof PLGA‐collagen hybrid scaffold. The cell leakproof PLGA‐collagen hybrid scaffolds should be useful for applications in cartilage tissue engineering. © 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2010 相似文献
820.
Inubushi T Kawazoe A Miyauchi M Kudo Y Ao M Ishikado A Makino T Takata T 《The Journal of biological chemistry》2012,287(28):23527-23536
Lactoferrin (LF) is an important modulator of the immune response and inflammation. It has also been implicated in the regulation of bone tissue. In our previous study we demonstrated that bovine LF (bLF) reduces LPS-induced bone resorption through a reduction of TNF-α production in vivo. However, it was not known how bLF inhibits LPS-mediated TNF-α and RANKL (receptor activator of nuclear factor κB ligand) production in osteoblasts. In this study we show that bLF impairs LPS-mediated TNF-α and RANKL production. bLF inhibited LPS-mediated osteoclastogenesis via osteoblasts in a co-culture system. Furthermore, bLF pretreatment inhibited LPS-induced NFκB DNA binding activity as well as IκBα and IKKβ (IκB kinase β) phosphorylation. MAP kinase activation was also inhibited by bLF pretreatment. However, bLF pretreatment failed to block the degradation of IRAK1 (interleukin-1 receptor-associated kinase 1), which is an essential event after its activation. Remarkably, we found that bLF pretreatment inhibited LPS-mediated Lys-63-linked polyubiquitination of TNF receptor-associated factor 6 (TRAF6). We also found that bLF is mainly endocytosed through LRP1 (lipoprotein receptor-related protein-1) and intracellular distributed bLF binds to endogenous TRAF6. In addition, bLF inhibited IL-1β- and flagellin-induced TRAF6-dependent activation of the NFκB signaling pathway. Collectively, our findings demonstrate that bLF inhibits NFκB and MAP kinase activation, which play critical roles in chronic inflammatory disease by interfering with the TRAF6 polyubiquitination process. Thus, bLF could be a potent therapeutic agent for inflammatory diseases associated with bone destruction, such as periodontitis and rheumatoid arthritis. 相似文献