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The BMP4-Smad Signaling Pathway Regulates Hyperandrogenism Development in a Female Mouse Model

The BMP4-Smad Signaling Pathway Regulates Hyperandrogenism D...

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中国生物化学与分子生物学会第十二届全国会员代表大会暨2018年全国学术会议

作者： Yang Liu Shao-Yue Du Meng Ding Xin Dou Fei-Fei Zhang Zhi-Yong Wu Shu-Wen Qian Wei Zhang Qi-Qun Tang Cong-Jian Xu Shanghai Key Laboratory of Female Reproductive Endocrine Related Disease Obstetrics and Gynecology HospitalFudan University Key Laboratory of Metabolism and Molecular Medicine the Ministry of EducationDepartment of Biochemistry and Molecular BiologyFudan University Shanghai Medical College

Polycystic ovary syndrome(PCOS) is a common endocrine disorder and a major cause of anovulatory sterility in women at reproductive *** patients with PCOS have hyperandrogenism,caused by excess androgen *** morphogenetic protein 4(BMP4) is an essential regulator of embryonic development and organ formation,and recent studies have also shown that BMP4 may be involved in female steroidogenesis ***,effect of BMP4 on hyperandrogenism remains ***,using a female mouse model of hyperandrogenism,we found that ovarian BMP4 levels were significantly decreased in *** androgens inhibited BMP4 expression via activation of androgen ***,BMP4 treatment suppressed androgen synthesis in theca cells and promoted estrogen production in granulosa cells,by regulating the expression of steroidogenic enzymes,including CYP11 A,HSD3 B2,CYP17 A1 and CYP19 ***,knockdown of BMP4 augmented androgen level and inhibited estrogen ***,Smad signaling rather than the p38 MAPK pathway regulated androgen and estrogen formation,thereby mediating the effect of *** note,BMP4-transgenic mice were protected against *** observations clarify a vital role of BMP4 in controlling sex hormone levels,and offer new insights into intervention for managing hyperandrogenism by targeting the BMP4-Smad signaling pathway.

关键词： endocrinology polycystic ovary syndrome hyperandrogenism BMP4 Smad cytochrome P450

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Crystal structure of the post-fusion core of the Human coronavirus 229E spike protein at 1.86 ? Resolution

Crystal structure of the post-fusion core of the Human coron...

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中国生物化学与分子生物学会第十二届全国会员代表大会暨2018年全国学术会议

作者： Lei Yan Bing Meng Jiangchao Xiang Ian A.Wilson Bei Yang Shanghai Institute for Advanced Immunochemical Studies ShanghaiTech University School of Life Science and Technology ShanghaiTech University Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences University of Chinese Academy of Sciences Department of Integrative Structural and Computational Biology and the Skaggs Institute for Chemical Biology The Scripps Research Institute

Human coronavirus 229 E(HCoV-229 E) usually causes mild upper respiratory infections in heathy adults,but may lead to severe complications or mortality in individuals with weakened immune *** entry of HCoV-229 E is mediated by its spike(S) protein,where the S1 domain facilitates attachment to host cells and the S2 domain is involved in subsequent fusion of the virus and host *** the fusion process,two heptad repeats,HR1 and HR2,in the S2 domain assemble into a six-helix membrane-fusion structure termed the fusion ***,the complete fusion-core structure of HCoV-229 E is presented at 1.86 ? resolution,representing the most complete post-fusion conformation thus far among published human alpha-coronavirus(α-HCoV) fusion-core *** overall structure of the HCoV-229 E fusion-core is similar to those of SARS,MERS and HCoV-NL63,but the packing of its 3 HR1 core differs from those of SARS and MERS in that it contains more noncanonical ‘x' and ‘da' ***-by-side electrostatic surface comparisons reveal that the electrostatic surface potentials are opposite in α-HCoVs and β-HCoVs at certain positions and that the HCoV-229 E surface also appears to be the most hydrophobic among the various *** addition to the highly conserved hydrophobic interactions between HR1 and HR2,some polar and electrostatic interactions are also well preserved across different *** study adds to the structural profiling of HCoVs to aid in the structure-based design of pan-coronavirus small molecules or peptides to inhibit viral fusion.

关键词： Coronavirus HCoVs-229E spike protein post-fusion core x-ray structure

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A fragment activity assay reveals the key residues of TBC1D15 GTPase-activating protein(GAP) in Chiloscyllium plagiosum

A fragment activity assay reveals the key residues of TBC1D1...

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中国生物化学与分子生物学会第十二届全国会员代表大会暨2018年全国学术会议

作者： Yangyang Jin Yanna Chen Jianqing Chen Dan Wang Hengbo Shi Hui Fei Zhengbing Lv Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine College of Life ScienceZhejiang Sci-Tech University

GTPase-activating proteins(GAPs) with a TBC(Tre-2/Bub2/Cdc16) domain architecture serve as negative regulators of Rab ***,we analyzed the Rab-GAP specificity of TBC1 D15 in the evolution and influence of key amino acid residue mutations on Rab-GAP *** alignment showed that five arginine residues of the TBC1 D15-GAP domain are conserved among the species Sus/Mus/Homo but have been replaced by glycine or lysine in Shark.A fragment activity assay was conducted by altering the five residues of Shark TBC1 D15-GAP to arginine,and the corresponding arginine in TBC1 D15 GAP domains from Sus and Homo species were mutated to resemble Shark TBC1 *** data revealed that the residues of G28,K45,K119,K122 and K221 in the Shark TBC1 D15-GAP domain had a key role in determining the specificity for Rab7 and *** of the five residues significantly altered the Shark TBC1 D15-GAP *** results revealed that the substrate specificity of TBC1 D15 had different mechanisms across the evolution of species from lower-cartilaginous fish to higher ***,the data support a different mechanism of Shark TBC1 D15-GAP in substrate selection,which imitates the function of Shark TBC1 D15-GAP in marine drug development.

关键词： TBC1D15 Rab-GAP activity evolution substrate specificity

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Archaeal NSun6 catalyzes m5C72 formation of tRNAs with wider specificity

Archaeal NSun6 catalyzes m5C72 formation of tRNAs with wider...

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中国生物化学与分子生物学会第十二届全国会员代表大会暨2018年全国学术会议

作者： Jing Li Ru-Juan Liu En-Duo Wang State Key Laboratory of Molecular Biology CAS Center for Excellence in Molecular Cell ScienceInstitute of Biochemistry and Cell BiologyShanghai Institutes for Biological SciencesChinese Academy of Sciences School of Life Science and Technology ShanghaiTech University

5-methylcytosine（m C） is a ubiquitous modification in DNA and different cellular *** mC72 modification was recently determined in the acceptor region of some specific tRNAs,establishing by human NSun6（hNSun6）.The homologs of hNSun6 are present only in higher eukaryotes and hyperthermophilic *** NSun6 homologs possess conserved catalytic residues,while have distinct difference in RNA recognition motifs from eukaryotic NSun6 *** now,the biochemical property and function of archaeal NSun6 homologs remain *** archaeon Pyrococcus horikoshii has one gene encoding an NSun6 homolog,*** found that PH1991 protein could catalyze mC72 formation on some specific Pht RNAs in vitro and was shown to be Ph ***,Ph NSun6 has much wider range of tRNA substrates than eukaryotic NSun6 s,attributing to its tRNA substrates specificity,which is elucidated by biochemical and crystallographic ***,the binding pocket for nucleotide 73 in Ph NSun6 is larger than that in hNSun6 to accommodate U73 or G73 containing PhtRNAs;Furthermore,Ph NSun6 lacks the eukaryotic NSun6 specific Lys-rich loop,resulting in the nonrecognition of D-stem region by Ph *** further found that mC72 modified tRNAs show higher thermal stability than their unmodified companions,but not affect the tRNA charging activity,highlighting the importance of wide-range tRNA mC72 modification in archaea.

关键词： m5C hNSun6 PhNSun6 thermal stability

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Structural and functional study of MLL3/MLL4 proteins

Structural and functional study of MLL3/MLL4 proteins

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中国生物化学与分子生物学会第十二届全国会员代表大会暨2018年全国学术会议

作者： Yanli Liu Su Qin Tsai-Yu Chen Ming Lei Aiping Dong Peter Loppnau Yanjun Li Min Gyu Lee Jinrong Min Hubei Key Laboratory of Genetic Regulation and Integrative Biology College of Life ScienceCentral China Normal University Structural Genomics Consortium University of Toronto Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer Center Department of Physiology University of Toronto

MLL3 and MLL4 are two closely related members of the SET1/MLL family of histone H3 K4 methyltransferase,and responsible for H3 K4 me1/2 methylation on enhancers that are essential in regulating cell-type-specific gene expression during cell *** of MLL3 and MLL4 have been reported in different types of ***,the PHD domains of MLL3/4 were reported to recruit the MLL3/4 complexes to their target genes by binding to histone H4 during the NT2/D1 stem cell *** we identified that an extended PHD domain(ePHD6) involving the sixth PHD domain and its preceding zinc finger in MLL3 and MLL4 specifically recognized the H4 H18 containing histone H4 fragment,and mutation and modifications of the fragment residues modulate its binding to MLL3/*** vitro methyltransferase assays further revealed that interaction between ePHD6 of MLL3/4 and histone H4 is required for their nucleosomal methylation *** domains have been reported to bind to N-terminus of histone *** study reveals a novel binding mode of the extended PHD domain of MLL3 with the H4H18 containing histone H4 fragment and provides insights into a transhistone regulatory mechanism of H3K4 methylation.

关键词： MLL3 PHD domain histone H4

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Effects of Soybean Extracts on the protein expressions of MMP-9 and TIMP-1 in atherosclerotic plaques of rabbits

Effects of Soybean Extracts on the protein expressions of MM...

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中国生物化学与分子生物学会第十二届全国会员代表大会暨2018年全国学术会议

作者： Jiang Qichang Xu Gang Huang Yue Lu Hongling Department of Thoracic Cardiac Surgery Affiliated Hospital of Zunyi Medical College

【Objective】 To investigate the effects of Soybean Extracts administration on the protein expression levels of matrix metalloproteinase-9(MMP-9) and tissue inhibitor of metalloproteinase-l(TIMP-l) in atherosclerotic plaques of rabbits.【Methods】 40 cases of paraffin-embedded tissue of atherosclerotic carotid arteries of rabbits,prepared by our research team members in the previous experiment,were divided into 5 groups including the control(n=8),model(n=8),as well as low(n=8),medium(n=8),and high-dose(n=8) groups of Soybean Extracts,the protein expressions of MMP-9 and TIMP-l were detected by immunohisto-chemical assay.【Results】The protein expression levels of MMP-9 and TIMP-1 were increased significantly and the ratios of TIMP-1/MMP-9 were decreased in the model group compared with the control group(p<0.05);While compared with the model group,the protein expression levelsof MMP-9 and TIMP-1 were decreased gradually and the ratios of TIMP-1/MMP-9 were increased in the low,medium,and high-dose groups(p<0.05).Pearson correlation analysis showed the negative-correlationship between the dosages of Soybean Extracts and the protein expression levels of MMP-9 and TIMP-1 in carotid atherosclerotic plaques of rabbits and the positive-correlationship between the dosages of Soybean Extracts and the ratios of TIMP-1/*** the correlation coefficients(r) were equal to-0.720,-0.831,and 0.870(p<0.05),respectively.【Conclusion】 Soybean Extracts decrease the protein expressions of MMP-9 and TIMP-1 and increase the ratios of TIMP-1/MMP-9 in carotid plaques of atherosclerotic rabbits that were caused by hyperhomocysteinemia(HHcy).And there were dosage-effect relationships between Soybean Extracts and the protein expression levels of MMP-9 and TIMP-1 as well as the ratios of TIMP-1/MMP-9 in carotid plaques of atherosclerotic rabbits that were caused by HHcy.

关键词： atherosclerosis matrix metalloproteinase-9 tissue inhibitor of metalloproteinase-1 soybean extracts

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Insights into the Structure and the DNA-Binding Mechanism of Human TGIF1 Homeodomain

Insights into the Structure and the DNA-Binding Mechanism of...

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中国生物化学与分子生物学会第十二届全国会员代表大会暨2018年全国学术会议

作者： Jiang Zhu Shuangli Li Rui Hu Yunhuang Yang State Key Laboratory of Magnetic Resonance and Atomic Molecular Physics Wuhan Institute of Physics and MathematicsChinese Academy of sciences University of Chinese Academy of Sciences

The TG interacting factor-1（TGIF1） protein in human is a transcription factor with essential roles in cell fate determination,and has been implicated in many human diseases including holoprosencephaly（HPE） and *** function of TGIF1 in transcriptional regulation depends on its homeodomain（HD） that binds DNA in a sequence-specific *** this work,the structure and the DNA-binding mechanism of TGIF1 HD were *** this study,the solution NMR structure of TGIF1 HD was determined,and based on this structure,the underlying causes for two HPE cases that respectively contained P192 A and R219 C mutation in TGIF1 HD were revealed.P192 and R219 were found to play roles in packing α1 and α2 helix to α3 helix together with A190 and F215 through side-chain interactions.P192 A and R219 C mutations led to structure disturbances of TGIF1 HD,which subsequently markedly reduced the DNA-binding affinity of TGIF1 ***,the α3 helix of TGIF1 HD was determined as the specific DNA-binding interface using hydrogen-deuterium exchange mass spectrometry（HDX-MS） and chemical exchange saturation transfer（CEST） *** results also suggested that the interface underwent a slow exchange between free and specific DNA-bound states at a rate of 130.2 ± 3.6 *** residues R220 and R221 located in the interface are crucial for the DNA binding and were supposed to account for the DNA binding *** study provides structural insights of the probable pathogenesis mechanism of two TGIF1-related HPE cases,and the structural and dynamic insights into the specific DNA-binding mechanism of TGIF1 HD.

关键词： NMR structure CEST HDX-MS Conformational dynamics

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Glabridin suppresses migration of human colorectal cancer cells through down-regulating myosin light chain phosphorylation via JNK1/2 signaling pathway

Glabridin suppresses migration of human colorectal cancer ce...

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中国生物化学与分子生物学会第十二届全国会员代表大会暨2018年全国学术会议

作者： Xiaoping Yang Li Zuo Duobing Zou Qing Zhou Zhen Liu Shuyu Gui Yuan Wang Laboratory of Molecular Biology and Department of Biochemistry Anhui Medical University

Background: Colorectal cancer(CRC) has one of the highest rates of cancer-related mortality,and investigating novel chemo-therapeutic approaches are significant in the treatment of colorectal *** is a potent anticancer agent in multiple types of human ***,its effect remains non-elucidated in colorectal ***: Human colon cancer cell lines(RKO and HCT116) were used to investigate the anti-cancer role of *** effects of glabridin on the viability,proliferation,migration and invasion of RKO and HCT116 cells were detected by MTT assay,plate colony formation assay,wound-healing asssay and transwell assay,***-scence was used to detect tight junction proteins(TJs)(occludin and ZO-1) expression and location in HCT116 *** protein expression levels were analyzed by western ***: Glabridin inhibited cell proliferative,migratory and invasive capacity of colorectal cancer *** expression of Rho-associated protein kinase(ROCK) and phospho(p)-myosin phosphatase targeting subunit 1(MYPT1) induced myosin light chain(MLC) phosphorylation level was markedly downregulated by ***,glabridin regulated p38 and JNK1/2 pathway in a time-dependent *** of ROCK and JNK1/2 by specific inhibitors also significantly enhanced glabridin-mediated migration inhibition and further attenuated the p-MYPT1 and ***,glabridin increased the expression of ZO-1 and occludin in the membrane of HCT116 cells,and glabridin induced the mesenchymal-epithelial transition,as determined by increased expression of the epithelial marker,E-cadherin,and decreased expression of the mesenchymal marker,***: In summary,these results indicated that glabridin inhibited migration in CRC by suppressing MLCP-dependent MLC phosphoryla-tion partly through JNK1/2 signaling pathway and could serve as a potential additional chemotherapeutic agent for treating CRC.

关键词： Glabridin Migration Invasion Colorectal cancer Myosin light chain phosphorylation

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Effect of physiological concentration of melatonin on the quality of stored erythrocyte in vitro

Effect of physiological concentration of melatonin on the qu...

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中国生物化学与分子生物学会第十二届全国会员代表大会暨2018年全国学术会议

作者： Shu Li Lihua Zhang Haiqing Yuan Yan Su Institute of blood conservation Baotou Medical College

Objective To investigate whether physiological concentration of melatonin(MT) has a protective effect on the stored red blood cell(RBCs) in *** Healthy adults were recruited,and 200 ml of whole blood was *** filtering white blood cells,plasma was removed by centrifugation,RBCs were resuspended in 50 ml MAP erythrocyte protective *** RBCs were gently mixed and then evenly distributed into 2 blood *** was added to one bag(MT group) to reach the final concentration of 150 pg/ml,and the other bag(control group) was added an equal volume of melatonin *** the bags were stored at 4 ℃.At shelf life of 0 day,7 day,14 day,21 day,28 day,35 day and 42 day,5 ml blood sample was taken and to detect RBCs morphology,RBCs Aggregation index,the relative hemolysis rate of RBCs,fraction of methemoglobin(FMetHb),the content of glucose(Glu),lactate(Lac),Malondialdehyde(MDA),ATP,pH,in order to observe whether MT has a protective effect on RBCs in *** Along with the increasing RBCs storage time,the quality of both groups of RBCs is ***,the deformed RBCs,aggregation index,relative hemolysis rate,malondialdehyde(MDA) and methemoglobin fraction(FMetHb) of MT group were significantly lower than those in control group,and the decreasing speed of pH was also lower than that of control group,and the difference was significant(P<0.05);the consumption of cGlu,ATP in MT group was lower than that in control group,at the same time cLac also lower than the control group,but the difference was not significant(P>0.05).Conclusion Physiological concentration of MT has the antioxidation function in *** can protect morphology,prevent hemolysis,reduce aggregation and slow down the decrease rate of *** is speculated that melatonin may effectively improve the preservation quality of RBCs through anti-oxidation,but the upper limit of physiological concentration of MT has no significant effect on the energy production and metabolism of RBC

关键词： Melatonin Red blood cells Blood preservation

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Different outcome of the PIWI-APC/C interplay during spermatogenesis and tumorigenesis

Different outcome of the PIWI-APC/C interplay during spermat...

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中国生物化学与分子生物学会第十二届全国会员代表大会暨2018年全国学术会议

作者： Shuang Zhao Lan-Tao Gou Feng Li Jun-Yan Kang Peng Yuan Mo-Fang Liu Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences-University of Chinese Academy of Sciences

PIWI proteins are known to enlist germline-specific Piwi-interacting RNAs(piRNAs) to suppress transposable elements and protect the integrity of the genome in germ *** recent studies showed that mouse PIWI(MIWI) interacts to APC/C E3 complex and is ubiquitinated by APC/C in late spermatids(Zhao et al.,Dev Cell 2013,24:13–25).Intriguingly,piRNA loading is essential for MIWI ubiquitination by APC/*** further showed that APC/C-mediated MIWI degradation releases RNF8,a histone E3 ligase,into the nucleus to mediate histone ubiquitination and subsequent histone-to-protamine exchange in late spermatids,while ubiquitination-deficient mutations in human Piwi(Hiwi) cause male infertility(Gou et al.,Cell 2017,169:1090-104).Interestingly,we found that the APC/C co-activator signature elements,i.e.C-box element and IR tail,are conserved in mammalian PIWI,and that both MIWI and HIWI can activate APC/C in vitro and in ***,Miwi C-box mutant male mice showed no detectable defects in fertility,suggesting that MIWI-mediated APC/C activation is not essential for *** note,HIWI is ectopically expressed in various types of human cancers,including pancreatic ductal adenocarcinomas(PDAC).Our data showed that HIWI acts as an oncoprotein in PDAC cells,whereas HIWI-mediated APC/C activation is required for HIWI in promoting PDAC metastasis but not tumor ***,ubiquitination and degradation of PNN,a cell adhesion-related molecule,by APC/CHIWI is largely responsible for HIWI in promoting PDAC *** together,our findings suggest that piRNA loading determines the outcome of PIWI-APC/C ***-loaded PIWI in late spermatids is subjected to ubiquitination and degradation by APC/C,while apo-PIWI without piRNAs in cancer cells functions as a co-activator to promote the degradation of a class of proteins by APC/C-ubiquitin pathway.

关键词： PIWI MIWI HIWI APC/C spermatogenesis tumorigenesis

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