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1.
Terminally misfolded proteins in the endoplasmic reticulum (ER) are retrotranslocated to the cytoplasm and degraded by proteasomes through a mechanism known as ER-associated degradation (ERAD). EDEM, a postulated Man8B-binding protein, accelerates the degradation of misfolded proteins in the ER. Here, EDEM was shown to interact with calnexin, but not with calreticulin, through its transmembrane region. Both binding of substrates to calnexin and their release from calnexin were required for ERAD to occur. Overexpression of EDEM accelerated ERAD by promoting the release of terminally misfolded proteins from calnexin. Thus, EDEM appeared to function in the ERAD pathway by accepting substrates from calnexin.  相似文献   

2.
Membrane and secretory proteins cotranslationally enter and are folded in the endoplasmic reticulum (ER). Misfolded or unassembled proteins are discarded by a process known as ER-associated degradation (ERAD), which involves their retrotranslocation into the cytosol. ERAD substrates frequently contain disulfide bonds that must be cleaved before their retrotranslocation. Here, we found that an ER-resident protein ERdj5 had a reductase activity, cleaved the disulfide bonds of misfolded proteins, and accelerated ERAD through its physical and functional associations with EDEM (ER degradation-enhancing alpha-mannosidase-like protein) and an ER-resident chaperone BiP. Thus, ERdj5 is a member of a supramolecular ERAD complex that recognizes and unfolds misfolded proteins for their efficient retrotranslocation.  相似文献   

3.
The mechanisms that determine how folding attempts are interrupted to target folding-incompetent proteins for endoplasmic reticulum-associated degradation (ERAD) are poorly defined. Here the alpha-mannosidase I-like protein EDEM was shown to extract misfolded glycoproteins, but not glycoproteins undergoing productive folding, from the calnexin cycle. EDEM overexpression resulted in faster release of folding-incompetent proteins from the calnexin cycle and earlier onset of degradation, whereas EDEM down-regulation prolonged folding attempts and delayed ERAD. Up-regulation of EDEM during ER stress may promote cell recovery by clearing the calnexin cycle and by accelerating ERAD of terminally misfolded polypeptides.  相似文献   

4.
刘泰麟  赵翔  李立新 《安徽农业科学》2012,40(4):1948-1955,2006
概述了蛋白质品质管理中涉及的分子伴侣、激发未折叠蛋白反应(unfolded protein response,UPR)和内质网相关性蛋白质降解途径(ER-associated degradation,ERAD)等的研究进展,并探讨了该领域存在的问题以及发展前景。指出蛋白质的生命过程经历生成、折叠、组装和降解,每个过程都有严格控制。内质网中,各种蛋白质合成、折叠并经修饰形成具有一定构象的功能性蛋白。其在内质网折叠受阻碍时,未折叠的蛋白聚集,激发UPR,使一系列分子伴侣和蛋白质折叠所需修饰酶类表达上调,帮助其完成折叠和装配。如果这些蛋白仍不能正确折叠,则进入ERAD被降解。  相似文献   

5.
概述了蛋白质品质管理中涉及的分子伴侣、激发未折叠蛋白反应(unfolded protein response, UPR)和内质网相关性蛋白质降解途径(ER-associated degradation, ERAD)等的研究进展,并探讨了该领域存在的问题以及发展前景。指出蛋白质的生命过程经历生成、折叠、组装和降解,每个过程都有严格控制。内质网中,各种蛋白质合成、折叠并经修饰形成具有一定构象的功能性蛋白。其在内质网折叠受阻碍时,未折叠的蛋白聚集,激发 UPR,使一系列分子伴侣和蛋白质折叠所需修饰酶类表达上调,帮助其完成折叠和装配。如果这些蛋白仍不能正确折叠,则进入 ERAD 被降解。  相似文献   

6.
【目的】在植物中,内质网胁迫(endoplasmic reticulum stress,ERS)和未折叠蛋白应答(unfolded protein response,UPR)参与环境胁迫响应过程,然而,玉米种子老化过程中内质网胁迫相关基因表达情况尚未见报道。文章利用基因数字表达谱技术探究玉米种子老化过程中内质网胁迫相关基因表达规律,以期为揭示种子衰老的分子机制提供理论依据。【方法】以玉米杂交种郑单958种子为材料,采用高温(45℃)高湿(相对湿度100%)的方法进行人工老化处理。分别提取未老化处理(对照)和老化处理3 d的玉米种胚总RNA,利用Illumina HiSeqTM 2000平台进行高通量测序。去除原始数据中的接头序列、包含模糊碱基的序列以及低质量序列,获得Clean reads,利用短序列比对软件SOAPaligner/ SOAP2将Clean Reads分别比对到玉米参考基因组和参考基因序列,采用RPKM(reads per kb per million reads)方法计算基因的表达量,根据FDR(false discovery rate)<0.001和|log2 ratio(T/CK)|≥1的标准筛选差异表达的基因,对获得的差异表达基因(differentially expressed genes,DEGs)进行KEGG(kyoto encyclopedia of genes and genomes)数据库功能注释分析,筛选出响应人工老化的内质网胁迫相关差异表达基因。利用qRT-PCR技术定量分析内质网胁迫相关基因在不同人工老化时间内的表达特性。【结果】基因数字表达谱鉴定结果表明,有104个差异表达基因在人工老化过程中参与内质网蛋白质加工(protein processing in endoplasmic reticulum)通路,其中内质网胁迫相关基因有97个(81个上调表达,16个下调表达)。对差异表达基因功能注释分析表明,内质网胁迫的标志性蛋白基因BiP以及分子伴侣蛋白基因CRTCNTGRP94等显著上调表达。参与内质网相关性降解(endoplasmic reticulum-associated degradation,ERAD)途径的有83个差异表达基因(70个上调,13个下调),其中启动ERAD途径的关键酶基因EDEM (ER degradation enhancing mannosidase I-like protein)下调,参与蛋白泛素化的E2泛素结合酶基因UbcH5、E3泛素连接酶基因Hrd1Doa10等也发生显著的表达变化。qRT-PCR结果表明,内质网胁迫相关基因在不同人工老化时间内表现表达多样性和复杂性。【结论】人工老化处理能造成玉米种胚细胞发生内质网胁迫。细胞通过上调分子伴侣基因表达和诱导ERAD途径响应内质网胁迫,但ERAD途径受阻可能引起错误折叠蛋白聚集,从而进一步加剧细胞损伤,最终导致种子活力降低甚至丧失。  相似文献   

7.
8.
A nonlysosomal pathway exists for the degradation of newly synthesized proteins retained within the endoplasmic reticulum (ER). This pathway is extremely selective: whereas some proteins are rapidly degraded, others survive for long periods in the ER. The question of whether this selectivity is due to the presence within the sensitive proteins of definable peptide sequences that are sufficient to target them for degradation has been addressed. Deletion of a carboxyl-terminal sequence, comprising the transmembrane domain and short cytoplasmic tail of the alpha chain of the T cell antigen receptor (TCR-alpha), prevented the rapid degradation of this polypeptide. Fusion of this carboxyl-terminal sequence to the extracellular domain of the Tac antigen, a protein that is normally transported to the cell surface where it survives long-term, resulted in the retention and rapid degradation of the chimeric protein in the ER. Additional mutagenesis revealed that the transmembrane domain of TCR-alpha alone was sufficient to cause degradation within the ER. This degradation was not a direct consequence of retention in the ER, as blocking transport of newly synthesized proteins out of the ER with brefeldin A did not lead to degradation of the normal Tac antigen. It is proposed that a 23-amino acid sequence, comprising the transmembrane domain of TCR-alpha, contains information that determines targeting for degradation within the ER system.  相似文献   

9.
Walter P  Ron D 《Science (New York, N.Y.)》2011,334(6059):1081-1086
The vast majority of proteins that a cell secretes or displays on its surface first enter the endoplasmic reticulum (ER), where they fold and assemble. Only properly assembled proteins advance from the ER to the cell surface. To ascertain fidelity in protein folding, cells regulate the protein-folding capacity in the ER according to need. The ER responds to the burden of unfolded proteins in its lumen (ER stress) by activating intracellular signal transduction pathways, collectively termed the unfolded protein response (UPR). Together, at least three mechanistically distinct branches of the UPR regulate the expression of numerous genes that maintain homeostasis in the ER or induce apoptosis if ER stress remains unmitigated. Recent advances shed light on mechanistic complexities and on the role of the UPR in numerous diseases.  相似文献   

10.
The segregation of secretory proteins into the cisternae of the endoplasmic reticulum (ER) is normally tightly coupled to their synthesis. This feature distinguishes their biogenesis from that of proteins targeted to many other organelles. In the examples presented, translocation across the ER membrane is dissociated from translation. Transport, which is normally cotranslational, may proceed in the absence of chain elongation. Moreover, translocation across the ER membrane does not proceed spontaneously since, even in the absence of protein synthesis, energy substrates are required for translocation. These conclusions have been extended to the cotranslational integration of newly synthesized transmembrane proteins.  相似文献   

11.
Nascent polypeptides emerging from the ribosome and not yet folded may at least transiently present degradation signals similar to those recognized by the ubiquitin system in misfolded proteins. The ubiquitin sandwich technique was used to detect and measure cotranslational protein degradation in living cells. More than 50 percent of nascent protein molecules bearing an amino-terminal degradation signal can be degraded cotranslationally, never reaching their mature size before their destruction by processive proteolysis. Thus, the folding of nascent proteins, including abnormal ones, may be in kinetic competition with pathways that target these proteins for degradation cotranslationally.  相似文献   

12.
G protein pathways   总被引:3,自引:0,他引:3  
  相似文献   

13.
14.
The 26S proteasome mediates degradation of ubiquitin-conjugated proteins. Although ubiquitin is recycled from proteasome substrates, the molecular basis of deubiquitination at the proteasome and its relation to substrate degradation remain unknown. The Rpn11 subunit of the proteasome lid subcomplex contains a highly conserved Jab1/MPN domain-associated metalloisopeptidase (JAMM) motif-EX(n)HXHX(10)D. Mutation of the predicted active-site histidines to alanine (rpn11AXA) was lethal and stabilized ubiquitin pathway substrates in yeast. Rpn11(AXA) mutant proteasomes assembled normally but failed to either deubiquitinate or degrade ubiquitinated Sic1 in vitro. Our findings reveal an unexpected coupling between substrate deubiquitination and degradation and suggest a unifying rationale for the presence of the lid in eukaryotic proteasomes.  相似文献   

15.
Degradation of proteins with acetylated amino termini by the ubiquitin system   总被引:11,自引:0,他引:11  
A free NH2-terminal group has been previously shown to be an obligatory signal for recognition and subsequent degradation of proteins in a partially fractionated and reconstituted ubiquitin proteolytic system. Naturally occurring proteins with acetylated NH2-termini--most cellular proteins fall in this category--were not degraded by this system. Other studies have suggested that the identity of the NH2-terminal residue is important in determining the metabolic stability of a protein in vivo (N-end rule). Whole reticulocyte lysate and antibodies directed against the ubiquitin-activating enzyme (E1) have now been used to show that such acetylated proteins are degraded in a ubiquitin-dependent mode. Although fractionation of lysate does not affect its proteolytic activity toward substrates with free NH2-termini, it completely abolishes the activity toward the blocked substrates, indicating that an important component of the system was either removed or inactivated during fractionation. An NH2-terminal "unblocking" activity that removes the blocking group, thus exposing a free NH2-terminus for recognition according to the N-end rule, does not seem to participate in this pathway. Incubation of whole lysate with labeled histone H2A results in the formation of multiple ubiquitin conjugates. In contrast, the fractionated system is devoid of any significant conjugating activity. These results suggest that a novel conjugating enzyme (possibly a ubiquitin-protein ligase) may be responsible for the degradation of these acetylated proteins by recognizing structural features of the substrate that are downstream and distinct from the NH2-terminal residue.  相似文献   

16.
17.
To identify previously unknown small molecules that inhibit cell cycle machinery, we performed a chemical genetic screen in Xenopus extracts. One class of inhibitors, termed ubistatins, blocked cell cycle progression by inhibiting cyclin B proteolysis and inhibited degradation of ubiquitinated Sic1 by purified proteasomes. Ubistatins blocked the binding of ubiquitinated substrates to the proteasome by targeting the ubiquitin-ubiquitin interface of Lys(48)-linked chains. The same interface is recognized by ubiquitin-chain receptors of the proteasome, indicating that ubistatins act by disrupting a critical protein-protein interaction in the ubiquitin-proteasome system.  相似文献   

18.
The physiological mechanism of maintaining the green colour of pak choy leaves (Brassica rapa var chinensis) with heat-shock treatment was studied. Chlorophyll in the outer leaves of pak choy degraded rapidly during storage at ambient temperature (20 ± 2℃), a slight yellow appeared. Heat-shock treatment (46- 50℃) had a mild effect on maintaining the green colour of outer leaves. Normal chlorophyll degradation was associated with a binding of chlorophyll with chlorophyll-binding-protein preceding chlorophyll breakdown.Heat-shock treatment was found to reduce the binding-capacity between chlorophyllbinding-protein and chlorophyll. In the chlorophyll degradation pathway, pheide dioxygenase was synthesized during leaf senescence which was considered to be a key enzyme in chlorophyll degradation. Activity of this enzyme was reduced following heat-shock treatment, which might explain the observed reduction in chlorophyll breakdown. Two groups of heat-shock proteins were detected in treated leaves, the first group containing proteins from 54KDa to 74 Kda, and the second group contained proteins from 15 KDa to 29KDa. Heat-shock treatment was also found to retard the decline of glucose and fructose (the main energy substrates) of outer leaves.  相似文献   

19.
Little is known about the identity of endoplasmic reticulum (ER) export signals and how they are used to regulate the number of proteins on the cell surface. Here, we describe two ER export signals that profoundly altered the steady-state distribution of potassium channels and were required for channel localization to the plasma membrane. When transferred to other potassium channels or a G protein-coupled receptor, these ER export signals increased the number of functional proteins on the cell surface. Thus, ER export of membrane proteins is not necessarily limited by folding or assembly, but may be under the control of specific export signals.  相似文献   

20.
Control of directionality in lambda site specific recombination   总被引:37,自引:0,他引:37  
The simple relation between the substrates and products of site-specific recombination raises questions about the control of directionality often observed in this class of DNA transactions. For bacteriophage lambda, viral integration and excision proceed by discrete pathways, and DNA substrates with the intrinsic property of recombining in only one direction can be constructed. These pathways display an asymmetric reliance on a complex array of protein binding sites, and they respond differently to changes in the concentrations of the relevant proteins. The Escherichia coli protein integration host factor (IHF) differentially affects integrative and excisive recombination, thereby influencing directionality. A four- to eightfold increase in intracellular IHF coincides with the transition from exponential to stationary phase; this provides a mechanism for growth phase-dependent regulation of recombination that makes the cellular physiology an intrinsic part of the recombination reaction.  相似文献   

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