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肽酰基精氨酸脱亚氨酶4(PAD4)催化肽酰精氨酸残基转变为肽酰瓜氨酸残基,其活性失调与类风湿性关节炎(RA)的发生与发展有关.目前PAD4被认为是开发新RA治疗药物的一种新靶酶.认识PAD4的结构与可能的作用机制,对于开发新RA治疗药物是重要的. 相似文献
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瓜氨酸化(citrullination)是指在蛋白质精氨酸脱亚胺酶(peptidylarginine deiminases,PADs)作用下蛋白质肽链中的精氨酸残基转化为瓜氨酸残基的过程,是一种重要的蛋白质翻译后修饰的过程。目前,已有5种PAD酶在人体组织中被发现,分别为PAD1~4和PAD6,PAD2和PAD4在许多恶性肿瘤组织中呈高表达。研究发现组蛋白、细胞角蛋白、纤维粘连蛋白、白介素8等蛋白质均可被瓜氨酸化,并与肿瘤细胞的增殖、分化、凋亡、迁移等密切相关。本文从表观遗传学观点出发就PADs介导的蛋白质瓜氨酸化与肿瘤关系的研究进展进行综述,为深入探讨肿瘤的发生发展机制及其治疗提供新的研究思路。 相似文献
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以HLAⅡ类转基因鼠研究类风湿关节炎的发病机制 总被引:1,自引:0,他引:1
类风湿关节炎(RA)是一种常见的慢性自身免疫性疾病,至今发病原因不明。许多研究表明遗传因素是导致RA发病的最主要原因,而在遗传因素中约35%来自于人类白细胞抗原(HLA)Ⅱ类复合体。因此,对于HLA Ⅱ类复合体参与RA发病的分子机制研究一直是人们关注的热点,而表达HLA Ⅱ类分子的转基因鼠是研究HLA Ⅱ类复合体与RA发病关系最佳的平台。目前,国外已建立了几个HLA Ⅱ类转基因鼠品系,为RA发病机制的研究奠定了很好的基础。本文对HLA Ⅱ类转基因鼠及以此为基础的RA相关研究进行综述。 相似文献
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《中国细胞生物学学报》2010,(5)
类风湿性关节炎(Rheumatoid Arthritis,RA)的发病机制尚未明确,但遗传因素和环境因素在RA的发病中起着重要作用。近三十年来,RA的发病机制与EBV(Epstein-Barr virus,又称HHV-4)感染的关联性已成为研究热点。诸多文献表明,RA患者的EBV抗体滴度高于正常对照组,血清中还存在着抗瓜氨酸化EBV肽的抗体,而RA患者体内的淋巴细胞却对EBV的应答呈现免疫低反应性。采用PCR、原位杂交和免疫组化等技术发现RA患者滑膜同样存在着EBV抗体及遗传物质,尽管有些研究结果仍不一致。一些EBV抗体与患者自身组织和细胞间存在氨基酸序列的同源性,如HLA-DRB1*0401/0405与EBV gp110糖蛋白存在同源序列的QKRAARA。基于上述证据提示EBV可能通过"分子模拟(molecular mimicry)"机制介导了RA的发病。另外,SAP(signallinglymphocyte activation molecule-associated protein,信号淋巴细胞活化分子相关蛋白)信号途径的异常可能也是EBV导致RA发生发展的分子生物学机制之一。尽管EBV同RA之间存在着诸多的联系,但仍需提供更多的实验证据阐明它们的因果关系。揭示RA发病与EBV感染的免疫学本质对临床防治RA有着十分重要的科学意义。 相似文献
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蛋白质精氨酸甲基转移酶(protein arginine methyltransferases,PRMTs)是真核生物中常见的一种酶,可催化组蛋白和非组蛋白底物中的精氨酸残基发生甲基化。在人类的基因组中,PRMTs由9个基因编码。作为最主要的II型精氨酸甲基转移酶,PRMT5是PRMT家族成员之一,参与了包括信号转导、转录调控、RNA剪切及DNA损伤修复在内的多种生物学过程;在多种人类恶性肿瘤中表达上调,发挥着类似致癌基因的作用。该文对PRMT5在多种癌症中的研究进展进行综述,并对现有的PRMT5小分子抑制剂进行总结(包括其结构和潜在的癌症靶向治疗应用前景)。 相似文献
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利用p53蛋白质核心区晶体结构作分子动力学发现,除了生化方面的稳定性之外,该区还具有分子力学上的高度稳定性.在此基础上作的R249残基替换分子动力学研究显示,p53蛋白质核心区249位点精氨酸被其他残基替换后能引起p53蛋白质核心区L2、L3结构域间的密切联系趋于松散,正常的空间构象发生改变并使整个核心区结构稳定性受到破坏.这一研究从三维结构变化上,直观地解释了R249残基替换造成的p53蛋白质免疫和生化特性改变的结构机制. 相似文献
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Anti-citrullinated collagen type I antibody is a target of autoimmunity in rheumatoid arthritis 总被引:6,自引:0,他引:6
Suzuki A Yamada R Ohtake-Yamanaka M Okazaki Y Sawada T Yamamoto K 《Biochemical and biophysical research communications》2005,333(2):418-426
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, but its autoimmune mechanisms are not clearly understood. Recently, anti-citrullinated peptide antibodies have been specifically observed in sera of RA patients. Furthermore, we identified RA-susceptible variant in a gene encoding citrullinating enzyme, peptidylarginine deiminase type 4 (PADI4). Therefore, we hypothesized that proteins which are modified in RA synovium by PADI4 act as autoantigens. Subsequently, we obtained human collagen type I (huCI) as one of the autoantigens using a RA synoviocyte cDNA library by immunoscreening. We also investigated that the levels of anti-citrullinated huCI were significantly higher in RA patient sera than in normal control sera with high specificity (99%) and positively correlated with the levels of anti-cyclic citrullinated peptide (anti-CCP) antibodies. We concluded that huCI is a novel substrate protein of PADIs and that citrullinated huCI is a candidate autoantigen of RA. 相似文献
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Hung HC Lin CY Liao YF Hsu PC Tsay GJ Liu GY 《Apoptosis : an international journal on programmed cell death》2007,12(3):475-487
Peptidylarginine deiminase IV (PADI4) posttranslationally converts peptidylarginine to citrulline. It plays an essential role
in immune cell differentiation and apoptosis. A haplotype of single-nucleotide polymorphisms (SNPs) in PADI4 is functionally
relevant as a rheumatoid arthritis (RA) gene. It could increase enzyme activity leading to raised levels of citrullinated
protein and stimulating autoantibody. Previously, our study showed that inducible PADI4 causes haematopoietic cell death.
Herein, we further investigate whether RA risk PADI4 haplotype (SNP PADI4; S55G, A82V and A112G) and the increase of its enzymatic
activity induce apoptosis. In the tetracycline (Tet)-On Jurkat T cells, ionomycin (Ion) only treatment didn't induce apoptosis however it promoted inducible PADI4-decreased cell viability and -enhanced apoptosis.
Through in vitro and in vivo PADI enzyme activity assay, we demonstrated that PADI4 enzyme activity of SNP PADI4 was higher than RA non-risk PADI4 haplotype
(WT PADI4). The effect of SNP PADI4-induced apoptosis was superior to WT PADI4. In addition, both Ion and SNP PADI4 synergistically provoked apoptosis were compared with both Ion and WT PADI4. Concurrently, in the conditionally inducible SNP PADI4 cells of Ion treatment-induced apoptosis, not only the expression of Bcl-xL was down-regulated and Bax up-regulated, but also cytochrome
c was released from mitochondria to cytoplasm in significant amounts. Western blotting data showed the increase in apoptosomal
caspase activation during programmed cell death in the inducible SNP PADI4 cells subsequent to Ion treatment. These data demonstrated that both SNP PADI4 increasing their enzyme activity could enhance apoptosis through the
mitochondrial pathway and further provide a conceivable explanation in the pathogenesis of RA following the upregulation of
PADI4 activity in its SNPs.
The authors (H.-C. Hung and C.-Y. Lin) contributed equally to this paper. 相似文献
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Peptidylarginine deiminase type 4: identification of a rheumatoid arthritis-susceptible gene 总被引:3,自引:0,他引:3
Recent studies using linkage disequilibrium and SNPs uncovered a rheumatoid arthritis (RA)-susceptible haplotype in the gene encoding peptidylarginine deiminase (PADI) type 4. This gene is one of four known PADI genes that encode enzymes to change arginine into citrulline in proteins. Post-translational modifications of proteins, including peptidyl citrullination, are related to autoimmunity, and peptidyl citrulline is a known target of one of the most RA-specific autoantibodies. Further research on PADI4, its citrullination of native peptides, subsequent breakdown of tolerance, and the role of these peptides in the development of RA, is expected to bring a better understanding of autoimmunity and arthritis, and advancements in the medical care of RA. 相似文献
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Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting 0.5–1% of the population worldwide. The disease has a
heterogeneous character, including clinical subsets of anti-citrullinated protein antibody (ACPA)-positive and APCA-negative
disease. Although the pathogenesis of RA is poorly understood, progress has been made in identifying genetic factors that
contribute to the disease. The most important genetic risk factor for RA is found in the human leukocyte antigen (HLA) locus.
In particular, the HLA molecules carrying the amino acid sequence QKRAA, QRRAA, or RRRAA at positions 70–74 of the DRβ1 chain
are associated with the disease. The HLA molecules carrying these “shared epitope” sequences only predispose for ACPA-positive
disease. More than two decades after the discovery of HLA-DRB1 as a genetic risk factor, the second genetic risk factor for
RA was identified in 2003. The introduction of new techniques, such as methods to perform genome-wide association has led
to the identification of more than 20 additional genetic risk factors within the last 4 years, with most of these factors
being located near genes implicated in immunological pathways. These findings underscore the role of the immune system in
RA pathogenesis and may provide valuable insight into the specific pathways that cause RA. 相似文献
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PADI4 post-translationally converts peptidylarginine to citrulline, a process called citrullination. Studies have demonstrated
the high expression of PADI4 in various malignant tumour tissues. PADI4 is also expressed at high levels in the blood of patients
with some malignant tumours. Thus far, citrullination of histone, cytokeratin, antithrombin and fibronectin have been confirmed
to be involved in abnormal apoptosis, high coagulation, and disordered cell proliferation and differentiation, all of which
are main features of malignant tumours. PADI4 is expressed in CD34+ stem cells in normal tissues, and many more CD34+ cells
expressing PADI4 are present in tumour tissues. These findings suggest that PADI4 may play an important role in tumourigenesis. 相似文献
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Comparison of enzymatic properties between hPADI2 and hPADI4 总被引:3,自引:0,他引:3
Nakayama-Hamada M Suzuki A Kubota K Takazawa T Ohsaka M Kawaida R Ono M Kasuya A Furukawa H Yamada R Yamamoto K 《Biochemical and biophysical research communications》2005,327(1):192-200
In the sera of rheumatoid arthritis (RA) patients, autoantibodies directed to citrullinated proteins are found with high specificity for RA. Peptidylarginine deiminases (PADIs) are enzymes responsible for protein citrullination. Among many isoforms of PADIs, only PADI4 has been identified as an RA-susceptibility gene. To understand the mechanisms of the initiation and progression of RA, we compared the properties of two PADIs, human PADI2 and human PADI4, which are present in the synovial tissues of RA patients. We confirmed their precise distribution in the RA synovium and compared the stability, Ca2+ dependency, optimal pH range, and substrate specificity. Small but significant differences were found in the above-mentioned properties between hPADI2 and hPADI4. Using LC/MS/MS analysis, we identified the sequences in human fibrinogen indicating that hPADI2 and hPADI4 citrullinate in different manners. Our results indicate that hPADI2 and hPADI4 have different roles under physiological and pathological conditions. Further studies are needed for the better understanding of the role of hPADIs in the initiation and progression of RA. 相似文献
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Katerina D. Samara Athina Trachalaki Eliza Tsitoura Anastasios V. Koutsopoulos Eleni D. Lagoudaki Ismini Lasithiotaki George Margaritopoulos Panagiotis Pantelidis Eleni Bibaki Nikolaos M. Siafakas Nikolaos Tzanakis Athol U. Wells Katerina M. Antoniou 《Respiratory research》2017,18(1):218