本文選題：線性泛素鏈組裝復(fù)合體LUBAC + 線性泛素鏈去泛素化酶OTULIN�。� 參考：《中國人民解放軍軍事醫(yī)學科學院》2016年博士論文

【摘要】：蛋白質(zhì)泛素化修飾過程在調(diào)節(jié)各種細胞生物學功能的過程中發(fā)揮了非常重要的作用,如細胞周期進程、DNA損傷修復(fù)、信號轉(zhuǎn)導(dǎo)和各種蛋白質(zhì)膜定位等。泛素化修飾可分為多聚泛素化修飾和單泛素化修飾。多聚泛素化修飾系統(tǒng)可以通過對底物連接不同類型的多泛素化鏈調(diào)節(jié)蛋白質(zhì)的功能。多聚泛素化修飾中已知7種泛素鏈連接方式均為泛素內(nèi)賴氨酸連接方式。近幾年發(fā)現(xiàn)了第8種類型的泛素鏈連接形式即線性泛素鏈,其泛素鏈的連接方式是由泛素甲硫氨酸的氨基基團與另一泛素甘氨酸的羧基基團相連形成泛素鏈標記。2006年日本大阪大學Kazuhiro Iwai教授實驗室首次發(fā)現(xiàn)了線性泛素鏈組裝復(fù)合體(Linear ubiquitin chain assembly complex,LUBAC)的存在,它是線性泛素化修飾的E3。LUBAC復(fù)合體是由HOIL-1L,HOIP,Sharpin組成。目前已知的線性泛素鏈組裝復(fù)合體的底物主要有NEMO、RIP2、RIP1等,它們在TNF-α激活的信號通路過程中發(fā)揮著非常重要的作用。LUBAC可參與多個信號通路的激活。LUBAC可以特異性激活NF-B信號通路,在ERK磷酸化激活過程也發(fā)揮著重要的作用。去泛素化酶屬于Ub信號的關(guān)鍵調(diào)節(jié)因子,目前已知去線性泛素化特異性DUB主要包含OTULIN(OTU domain-containing deubiquitinase with linear linkage specificity)可以對線性泛素鏈的多聚泛素化信號起到調(diào)節(jié)作用。去線性泛素化酶OTULIN在調(diào)控Wnt信號通路、神經(jīng)發(fā)育以及血管生成等多種生物學功能中發(fā)揮著重要作用。泛素化系統(tǒng)一般通過適時和有選擇性的在其底物上加上泛素鏈的方式調(diào)控細胞的功能,所以識別線性泛素鏈組裝復(fù)合體的底物和功能非常必要,它將有助于闡明線性泛素鏈參與調(diào)控的各種細胞生物學功能的具體機制。尋找新的參與體內(nèi)線性泛素化連接和識別的蛋白復(fù)合體,成為線性泛素化研究領(lǐng)域的熱點。解析LUBAC介導(dǎo)的線性泛素化是否參與其他信號通路以及識別LUBAC新底物同樣十分重要。Smurfs(Smad ubiquitination regulatory factor 1/2)是HECT E3 Nedd4家族的主要成員,目前報道參與多種細胞生物學的功能。Smurfs最初確定來源于調(diào)節(jié)BMP/TGFβ家族信號通路,但最近的研究表明,其調(diào)節(jié)范圍廣泛,包括Wnt信號通路調(diào)控。TGFβ家族信號通路調(diào)節(jié)廣泛的生物學過程包括細胞的遷移、生長、分化和發(fā)育。本課題組在研究Smurfs調(diào)控機制的過程中,利用酵母雙雜交技術(shù),通過Smurf2-HECT結(jié)構(gòu)域?qū)ζ⑴K文庫篩選得到HOIP(HOIL-1L Interacting Protein),HOIP作為線性泛素鏈組裝復(fù)合體LUBAC的核心分子,我們猜想Smurfs與HOIP是否存在真實的相互作用,同時Smurfs與LUBAC線性復(fù)合體有什么關(guān)聯(lián),Smurfs在線性泛素化的調(diào)控過程中是否發(fā)揮了重要的作用,LUBAC線性泛素化修飾是否參與新的信號通路調(diào)控發(fā)揮重要的功能,Smurfs是否在NF-κB信號通路的過程中發(fā)揮著重要的作用,這些問題將在本課題中展開深入的研究。本課題通過實驗研究發(fā)現(xiàn):Smurf2與Smurf1相似,都可以與HOIP互作。Smurfs作為泛素連接酶E3其活性位點突變體不影響其與HOIP的相互關(guān)系。Smurfs與LUBAC復(fù)合體的其他組分HOIL-1L,Sharpin不能直接相互作用,但是加入HOIP后Smurfs可以與HOIL-1L和Sharpin相互作用。體內(nèi)CO-IP實驗發(fā)現(xiàn)以Smurf1為例,HOIP、HOIL-1L、Sharpin均可以與Smurfs相互作用。HOIP是一個具有多結(jié)構(gòu)域分子量為120KD的蛋白,通過研究我們發(fā)現(xiàn)HOIP的C端的LDD結(jié)構(gòu)域可以與Smurf1-HECT-N-Lobe結(jié)合。LDD被稱為線性泛素決定區(qū),在所有RBR類E3中,LDD結(jié)構(gòu)域是特異存于HOIP,特異性決定線性泛素鏈組裝復(fù)合體LUBAC的功能。該結(jié)合區(qū)為泛素由E2轉(zhuǎn)移到泛素硫酯鍵中間體最后停留的位置,該區(qū)域中ZF結(jié)構(gòu)域可以與Ub結(jié)合。Smurfs作為一個泛素連接酶與線性泛素鏈組裝復(fù)合體LUBAC之間是否存在調(diào)控關(guān)系Smurfs是否參與線性泛素化修飾?我們發(fā)現(xiàn)單表達LUBAC復(fù)合體的各個組分,Smurfs表達水平不變,共表達LUBAC復(fù)合體的3個成員HOIP、HOIL-1L、Sharpin后,Smurfs蛋白表達水平下調(diào),LUBAC對于Smurfs E3活性突變體Smurf1 C699A和Smurf2C716A沒有影響。敲低LUBAC復(fù)合體的各個組分HOIP、HOIL-1L、Sharpin、Smurfs的表達水平上調(diào)。檢測Smurfs的泛素化水平,發(fā)現(xiàn)單一過表達HOIP,Smurfs的泛素化水平?jīng)]有變化,過表達LUBAC復(fù)合體后,Smurfs的泛素化水平明顯上調(diào)。敲低LUBAC復(fù)合體的各個組分HIOP/HOIL-1L/Sharpin后,Smurfs泛素化水平下調(diào),體外泛素化實驗同樣得到相同的結(jié)論。HOIP C885是LUBACE3活性中心,C885A突變體抑制Smurfs體外泛素化水平的上調(diào)。OTULIN作為線性去泛素化酶,可以抑制Smurfs泛素化水平的上調(diào)。Smurfs泛素水平上調(diào),被認為是LUBAC促進Smurfs募集線性泛素鏈使Smurfs發(fā)生線性泛素化修飾。LUBAC可以增強Smurfs E3活性的機制在于HOIP與Smurfs的相互作用抑制了Smurf1分子間二聚體形成,促進活性單體的比例,進而我們還發(fā)現(xiàn)LUBAC可以抑制TGFβ/BMP信號通路活性。敲低HOIP后,CAGA12-luc活性上調(diào),TGFβ信號通路相關(guān)的靶基因Smad7,SNON,CTGF,PAI-1表達上調(diào)。同時發(fā)現(xiàn),BMP激活的BRE-luc的活性被LUBAC抑制。LUBAC可以抑制TGFβ/BMP信號通路的活性的機制是什么?LUBAC復(fù)合體可以增強Smurfs的泛素化水平,那么對于Smurfs的重要底物R-Smad,具有怎么樣的重要作用呢,我們研究發(fā)現(xiàn)LUBAC線性泛素鏈組裝復(fù)合體可以加速Smurfs對Smads的降解,這一過程是依賴于Smurfs E3活性的。TGFβ促進細胞遷移、侵襲和轉(zhuǎn)移,那么LUBAC復(fù)合體與OTULIN對細胞遷移有什么作用呢?通過Transwell實驗,我們發(fā)現(xiàn)敲低HOIP以后可以增強細胞的遷移能力,相對地,敲低OTULIN后,細胞遷移能力降低,同時利用RT-PCR實驗發(fā)現(xiàn),有關(guān)細胞遷移、侵襲和轉(zhuǎn)移相關(guān)的TGFβ信號通路相關(guān)的靶基因PTHr P、MMP2、MMP9在HOIP敲低和OTULIN敲低的細胞中也發(fā)生相應(yīng)的上調(diào)和下調(diào)。綜上所述,本課題主要以HECT類泛素連接酶Smurfs通過與線性泛素鏈組裝復(fù)合體LUBAC核心分子HOIP的相互作用為聯(lián)系的基礎(chǔ),發(fā)現(xiàn)線性泛素鏈組裝復(fù)合體LUBAC可以通過線性泛素化修飾Smurfs,增強Smurfs E3活性,加速Smurfs的底物降解,抑制TGFβ/BMP信號通路的活性,相對地,我們也發(fā)現(xiàn)去線性泛素化酶OTULIN和LUBAC的C885A的E3活性突變體可以廢除Smurfs的泛素化增強效應(yīng)。LUBAC負調(diào)控TGFβ/BMP信號通路的活性,TGFβ促進細胞遷移、轉(zhuǎn)移,LUBAC抑制了該效應(yīng)。這是首次發(fā)現(xiàn)線性泛素鏈組裝復(fù)合體和線性泛素化修飾參與TGFβ/BMP信號通路的調(diào)控。我們也發(fā)現(xiàn)LUBAC可以促進Smurfs募集線性泛素化從而增強Smurfs E3的活性,這也是對Smurfs調(diào)控機制又一補充。Nedd8(neural precursor cell-expressed developmentally downregulated 8)分子是一類結(jié)構(gòu)上與泛素相似的分子,參與蛋白質(zhì)翻譯后修飾,這一過程被稱為Neddylation,Neddylation的發(fā)生機制與泛素化相似,需要E1(UBA3-APPBP1)、E2(Ubc12)、E3介導(dǎo)的一系列酶促反應(yīng)。Neddylation修飾在Cullin-Roc類泛素連接酶的活性調(diào)控中具有至關(guān)重要的作用。與泛素化研究相比,目前在真核細胞內(nèi)還只有很少的Neddylation修飾底物被發(fā)現(xiàn),Neddylation的生理功能也有待深入研究。目前對于Ub與底物的結(jié)合研究的比較清楚,已發(fā)現(xiàn)接近20種結(jié)構(gòu)域(即UBD)可以與泛素結(jié)合,但是對于類泛素蛋白Nedd8非共價結(jié)合蛋白的研究,目前鮮有報道,所以研究Nedd8與蛋白相互作用的特異性規(guī)律,可以更好的了解Neddylation的生理功能。Smurf1是HECT泛素連接酶Nedd4家族的成員,在骨形成、胚胎發(fā)育等過程中發(fā)揮重要作用。Smurf2與Smurf1高度相似,兩者負調(diào)控TGFβ和BMP信號通路。本課題以Smurf1為誘餌采用酵母雙雜交的方法,篩選到類泛素蛋白Nedd8。我們通過CO-IP、GST-Pull down等實驗證明Smurf1與Smurf2均可以與Nedd8在體內(nèi)外發(fā)生相互作用,利用截短體相互作用研究,我們發(fā)現(xiàn)Smurf1的WW結(jié)構(gòu)域,HECT的N-lobe Small結(jié)構(gòu)域,HECT的C-lobe結(jié)構(gòu)域可以結(jié)合Nedd8。Smurf2與Smurf1相似,HECT結(jié)構(gòu)域中的N-lobe Small domain和C-lobe介導(dǎo)結(jié)合,但是WW結(jié)構(gòu)域未參與與Nedd8的結(jié)合。分析Nedd4家族9個成員與Nedd8的相互作用發(fā)現(xiàn)NEDL1和NEDL2與Smurfs同樣可以結(jié)合Nedd8。隨后,我們利用Nedd8的晶體結(jié)構(gòu)與Smurf2-HECT晶體結(jié)構(gòu)進行結(jié)構(gòu)對接,模擬相互作用,以期發(fā)現(xiàn)結(jié)合模序。通過序列比對,序列L(X7)R(X5)F(X)ALQ保守。突變體相互作用實驗證明,該模序介導(dǎo)結(jié)合。通過突變體功能實驗表明廢除Nedd8與Smurf的非共價相互作用削弱了Smurf的Neddylation修飾,穩(wěn)定了Smurf蛋白水平,同時改變了Smurf與Ub形成硫酯鍵中間體的能力。Nedd8與Smurf相互作用對于Smurf的E3活性和底物的泛素化水平起到了關(guān)鍵作用。同時對于Smurfs所調(diào)控的BMP和TGFβ信號通路以及細胞遷移發(fā)揮了重要的作用。同時,我們也研究發(fā)現(xiàn)Nedd8可共價修飾Smurf。Smurf1可以作為一個Nedd8泛素連接酶激活Smurf1發(fā)生自身Neddylation修飾。Smurf1的N-lobe中的C426是其Neddylation E3催化活性中心,區(qū)別于泛素修飾E3活性中心C699。Neddylaiton對HECT E3調(diào)控過程中發(fā)揮重要作用。
[Abstract]:The process of ubiquitination of proteins plays a very important role in regulating various cell biological functions, such as cell cycle process, DNA damage repair, signal transduction and various protein membrane localization. Ubiquitination modification can be divided into polyubiquitin modification and mono ubiquitination modification. The substrate connects different types of polyubiquitin chains to regulate the function of proteins. The 7 ubiquitin chain connections in polyubiquitin modification are all ubiquitin lysine connections. In recent years, eighth types of ubiquitin chain connections, namely, linear ubiquitin chains, are found in the ubiquitin chain by the amino groups of the ubiquitin methionine. The existence of a linear ubiquitin chain assembly complex (Linear ubiquitin chain assembly complex, LUBAC) was first found in Professor Kazuhiro Iwai of Osaka University, Japan, for the first time linked to the carboxyl group of another ubiquitin glycine for.2006. The E3.LUBAC complex of the linear ubiquitination trimming is the HOIL-1L, HOIP, and group. The substrates of the linear ubiquitin chain assembly complexes known at present are mainly NEMO, RIP2, RIP1 and so on. They play a very important role in the signaling pathway of TNF- alpha activation..LUBAC can participate in the activation of.LUBAC pathway in multiple signaling pathways, and the activation process of ERK phosphorylation also plays an important role in the activation process of ERK phosphorylation. Use. De ubiquitination enzyme is a key regulator of Ub signal. Currently, the known de linear ubiquitination specific DUB contains OTULIN (OTU domain-containing deubiquitinase with linear linkage specificity), which can regulate the polyubiquitination signal of linear ubiquitin chain. Pathways, neurodevelopment, and angiogenesis play an important role. Ubiquitination systems generally regulate cell functions by adding a ubiquitin chain on their substrates by timely and selective substrates, so it is necessary to identify the substrates and functions of the linear ubiquitin chain assembly complex, which will help to clarify the linearity. The ubiquitin chain participates in the specific mechanisms of various cellular biological functions regulated by the ubiquitin chain. Finding new protein complexes involved in linear ubiquitination and recognition has become a hot spot in the field of linear ubiquitination. It is also very important to analyze whether LUBAC mediated linear ubiquitination is involved in other signaling pathways and identification of LUBAC NEW substrates. (Smad ubiquitination regulatory factor 1/2) is a major member of the HECT E3 Nedd4 family. Currently, the function.Smurfs involved in multiple cell biology is originally determined from the regulation of the BMP/TGF beta family signal pathway, but recent studies have shown that the regulatory range is wide, including Wnt signaling pathway regulating the regulation of the.TGF beta family signal pathway. Extensive biological processes include cell migration, growth, differentiation and development. In the process of studying the regulatory mechanism of Smurfs, we use yeast two hybrid technology to screen HOIP (HOIL-1L Interacting Protein) through the Smurf2-HECT domain to the spleen library, and HOIP as the core molecule of the linear ubiquitin chain assembly complex LUBAC. We conjecture whether there is a real interaction between Smurfs and HOIP, and what is the correlation between Smurfs and the LUBAC linear complex, and whether Smurfs plays an important role in the regulation of linear ubiquitination, and whether LUBAC linear ubiquitination modification plays an important role in the regulation of new signaling pathways, and whether Smurfs is in NF- kappa B signaling pathway. The problem will play an important role in the process. Through the experimental study, we find that Smurf2 is similar to Smurf1 and can interact with HOIP as.Smurfs as a ubiquitin ligase E3 its active site mutant does not affect its relationship with HOIP, the other component HOIL- of.Smurfs and LUBAC complex. 1L, Sharpin can not interact directly with each other, but after adding HOIP, Smurfs can interact with HOIL-1L and Sharpin. In vivo CO-IP experiment found that HOIP, HOIL-1L, Sharpin can interact with Smurfs as an egg white with a multi domain molecular weight. .LDD, which can be combined with Smurf1-HECT-N-Lobe, is called a linear ubiquitin decision area. In all RBR class E3, the LDD domain is specific to HOIP and specifically determines the function of the linear ubiquitin chain assembly complex LUBAC. The binding area is the final stop of ubiquitin from E2 to the ubiquitin thiol bond intermediate, and the ZF domain in this region can be with Ub knots. Is there a regulatory relationship between.Smurfs and LUBAC as a ubiquitin ligase and linear ubiquitin chain assembly complex? Is Smurfs involved in linear ubiquitination? We found that each component of the single expression of LUBAC complex, the Smurfs expression level is unchanged, and the expression of 3 members of the LUBAC complex, HOIP, HOIL-1L, Sharpin, Smurfs protein expression The level of LUBAC was not affected by the Smurfs E3 active mutant Smurf1 C699A and Smurf2C716A. The expression level of HOIP, HOIL-1L, Sharpin, Smurfs of the low LUBAC complex was up-regulated. The level of ubiquitination is obviously up-regulated. After knocking down each component of the LUBAC complex for HIOP/HOIL-1L/Sharpin, the level of ubiquitination of Smurfs is down. The same conclusion is found that.HOIP C885 is the active center of LUBACE3 in vitro. The C885A mutant inhibits the up-regulation of.OTULIN as a linear ubiquitination enzyme, which can inhibit the ubiquitination of Smurfs in vitro as a linear ubiquitination enzyme. The up regulation of Smurfs ubiquitination level up regulation of.Smurfs ubiquitin level, it is considered that LUBAC promotes Smurfs to raise linear ubiquitin chain to make Smurfs linear ubiquitination.LUBAC can enhance Smurfs E3 activity. The interaction between HOIP and Smurfs inhibits the formation of two polymer between Smurf1 molecules and promotes the proportion of active monomers. We also found that LUBAC can inhibit the activity of TGF beta /BMP signaling pathway. After knocking down HOIP, CAGA12-luc activity up-regulated. The target genes of the TGF beta signaling pathway, Smad7, SNON, CTGF and PAI-1 are up regulated. It can enhance the ubiquitination level of Smurfs, so how important is the important role of the Smurfs substrate R-Smad? We have found that the LUBAC linear ubiquitin chain assembly complex can accelerate the degradation of Smurfs to Smads. This process is dependent on the.TGF beta of Smurfs E3 activity to promote cell migration, invasion and metastasis, then LUBAC complex What is the effect of chimerism and OTULIN on cell migration? Through Transwell experiments, we found that after knocking down HOIP, the migration ability of cells could be enhanced. Relatively, after knocking down OTULIN, the cell migration ability decreased, and the RT-PCR experiment found the target gene PTHr P related to cell migration, invasion and metastasis associated TGF beta signaling pathway. MMP2, MMP9 also up-regulated and down-regulated at HOIP knockout and OTULIN knockout cells. To sum up, the topic is mainly based on the interaction of HECT ubiquitin ligase Smurfs with the interaction of the linear ubiquitin chain assembly complex LUBAC core molecule HOIP, and it is found that the linear ubiquitin chain assembly complex LUBAC can be linear through linear flooding. Modified Smurfs, enhanced the activity of Smurfs E3, accelerated the degradation of Smurfs substrate and inhibited the activity of TGF beta /BMP signaling pathway. Relatively, we also found that the C885A E3 active mutant of the linear ubiquitinase OTULIN and LUBAC can abolish the activity of Smurfs ubiquitination enhancement effect.LUBAC negatively regulated beta signaling pathway activity. Migration, transfer, and LUBAC inhibit this effect. This is the first time that the linear ubiquitin chain assembly complex and linear ubiquitination modification are involved in the regulation of the TGF beta /BMP signaling pathway. We also found that LUBAC can promote linear ubiquitination of Smurfs to enhance the activity of Smurfs E3, which is also a supplement to the Smurfs regulation mechanism (neural PRECUR). SOR cell-expressed developmentally downregulated 8) is a class of molecules similar to ubiquitin and participates in post-translational modification of protein. This process is called Neddylation, the mechanism of Neddylation is similar to ubiquitination, and a series of enzyme catalyzed reaction.Neddylation modified by E1 (UBA3-APPBP1), E2 (Ubc12) and E3 are modified. N-Roc ubiquitin ligase plays an important role in the regulation of the activity of ubiquitin ligase. Compared with ubiquitination, only a few Neddylation modified substrates have been found in eukaryotic cells, and the physiological function of Neddylation remains to be studied. At present, the study of the binding of Ub to substrates is clear and close to 20 structures have been found. The domain (UBD) can be combined with ubiquitin, but there are few reports on the non covalent binding protein of Nedd8 like ubiquitin protein. Therefore, the study of the specific rules of the interaction between Nedd8 and protein can better understand the physiological function of Neddylation,.Smurf1 is a member of the HECT ubiquitin linked enzyme Nedd4 family, in bone formation, embryo development and so on. The important role of.Smurf2 is highly similar to that of Smurf1, which negatively regulates the TGF beta and BMP signaling pathways. This subject uses Smurf1 as the bait using yeast two hybrid method to screen ubiquitin like protein Nedd8.. We have proved that Smurf1 and Smurf2 can interact with Nedd8 in vivo and in vivo by CO-IP, GST-Pull down and other experiments. The study of intertruncation interaction shows that the WW domain of Smurf1, the N-lobe Small domain of HECT, the C-lobe domain of HECT can be similar to Nedd8.Smurf2 and Smurf1, and the N-lobe Small in the HECT domain is combined with them. Interaction found that NEDL1 and NEDL2 can be combined with Smurfs to combine with Nedd8., and then we use the crystal structure of Nedd8 to simulate the structure of the Smurf2-HECT crystal structure and simulate the interaction, in order to find the binding order. By sequence alignment, the sequence L (X7) R (X5) F (X) is preserved. The experiment of mutants interaction proves that the model sequence is mediated by binding. The non covalent interaction between Nedd8 and Smurf weakened the Neddylation modification of Smurf, stabilized the Smurf protein level, and changed the ability of.Nedd8 and Smurf interaction between Smurf and Ub to form the sulfur ester bond intermediate, which played a key role in the E3 activity of Smurf and the ubiquitination of substrates. The BMP and TGF beta signaling pathways regulated by Smurfs and cell migration play an important role. At the same time, we also found that Nedd8 covalently modified Smurf.Smurf1 can be used as a Nedd8 ubiquitin ligase to activate Smurf1 to occur Neddylation modified.Smurf1 N-lobe C426 is its Neddylation catalytic active center. The ubiquitin modified E3 active center C699.Neddylaiton plays an important role in the regulation of HECT E3.
【學位授予單位】：中國人民解放軍軍事醫(yī)學科學院
【學位級別】：博士
【學位授予年份】：2016
【分類號】：Q75

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