OGT供体底物识别机制及其自身O-GlcNAc糖基化修饰功能的研究
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摘要
O-GlcNAc糖基化修饰是一种动态的蛋白质翻译后修饰,广泛存在于植物和动物中,能够影响蛋白的催化活性、亚细胞定位以及与其他蛋白之间的相互作用,参与细胞内的信号转导、能量代谢等重要的细胞生理活动,与多种慢性疾病相关。
O-GlcNAc糖基转移酶(OGT)负责催化O-GlcNAc糖基转移反应的发生。在人体内,OGT有三种亚型,即ncOGT、mOGT和sOGT,其结构的主要差异在于N末端TPR序列数目不同。由于三种亚型C末端催化结构域是完全相同的,因此其催化机制以及其与糖基供体的识别机制也应是相同的。因此在本课题中,我们选取了较为容易表达的sOGT作为研究对象,首先对其底物特异性进行了研究。以CKII十七肽为受体底物,我们探索sOGT对26种UDP-GlcNAc衍生物的催化活性。其中,UDP-6-deoxy-GlcNA、UDP-GlcNPr、UDP-6-deoxy-GalNAc和UDP-4-deoxy-GlcNAc四种化合物能够作为sOGT的供体底物。进一步对其中三种化合物的酶学常数的测定表明,UDP-GlcNAc糖基基团的C2位乙酰氨基上的取代、C6和C4位羟基的脱氧取代以及C4位羟基的异构都会削弱sOGT与供体底物的亲合力。通过OGT与底物的分子对接,并经定点突变验证,我们发现sOGT的Leu653的羰基氧和Thr560位的羟基能够与GlcNAc的C4/C6-OH形成氢键；Met501与UDP-GlcNAc的C2位乙酰氨基间的空间较小,不能容纳体积较大的取代基团,而其附近的疏水环境也利于疏水性取代基团的进入。上述结论为进一步了解OGT与糖基供体的相互作用以及其催化机制有一定帮助。
已有研究表明,OGT也可以作为自身催化O-GlcNAc糖基转移反应的底物,被糖基化修饰。基于O-GlcNAc修饰的功能,我们认为OGT的自身糖基化参与了对OGT功能的调控。
本课题运用多种生物学和化学研究方法对OGT的自身糖基化修饰现象进行了研究,发现了6个糖基化位点(S10, T12, S18, T38, S52, T449, T662),定点突变结果证实其中三个糖基化位点(S18,T38,T449)对sOGT糖基化水平有显著影响。通过对过表达的sOGT在细胞质和细胞核的分布及糖基化水平的研究发现,细胞质内sOGT的糖基化水平更高。通过激光共聚焦显微镜对不同sOGT突变体的亚细胞定位进行观察,与野生型相比较,发现T449A和T662A两个突变体转运入核明显减少,而其它突变体变化不大,这表明T449和T662两个位点可能与sOGT转运入核相关。通过Pull down技术以及生物质谱等研究方法,我们发现糖基化修饰对sOGT互作蛋白有显著影响,糖基化修饰sOGT能够作用的互作蛋白更多,差异蛋白中很多与重要的细胞生理活动相关。O-GlcNAc自身糖基化作为OGT自身调控机制的组成部分,其功能和作用机理尚不清晰,我们的研究对其中部分问题做出了解答,为进一步研究OGT自身调控机制奠定了基础,为OGT相关疾病发病机理的研究提供了参考。
O-GlcNAc modification, namely O-GlcNAcylation, is an essential post-translational modification with a single β-N-acetylglucosamine linked to Ser or Thr residues of various nucleocytoplasmic proteins. It contributes to various cellular cascades, including signal transduction, gene expression and protein trafficking. Dysregulation in O-GlcNAcylation is assumed to be tightly linked to chronic diseases, such as cancers, diabetes and neurodegenerative diseases.
O-Linked β-N-acetylglucosaminyl transferase (OGT) plays an important role in the glycosylation of proteins, which is involved in various cellular events. In human, three isoforms of OGT (short OGT [sOGT]; mitochondrial OGT [mOGT]; and nucleocytoplasmic OGT [ncOGT]) share the same catalytic domain, implying that they might adopt a similar catalytic mechanism, including sugar donor recognition. In this work, the sugar-nucleotide tolerance of sOGT was investigated. Among a series of uridine5'-diphosphate-N-acetylglucosamine (UDP-GlcNAc) analogs tested using the casein kinase Ⅱ(CKⅡ) peptide as the sugar acceptor, four compounds could be used by sOGT, including UDP-6-deoxy-GlcNAc, UDP-GlcNPr, UDP-6-deoxy-GalNAc and UDP-4-deoxy-GlcNAc. Determined values of Km showed that the substitution of the N-acyl group, deoxy modification of C6/C4-OH or epimerization of C4-OH of the GlcNAc in UDP-GlcNAc decreased its affinity to sOGT. A molecular docking study combined with site-directed mutagenesis indicated that the backbone carbonyl oxygen of Leu653and the hydroxyl group of Thr560in sOGT contributed to the recognition of the sugar moiety via hydrogen bonds. The close vicinity between Met501and the N-acyl group of GlcNPr, as well as the hydrophobic environment near Met501, were responsible for the selective binding of UDP-GlcNPr. These findings illustrate the interaction of OGT and sugar nucleotide donor, providing insights into the OGT catalytic mechanism.
Self-glycosylation of OGT was reported by several research groups. Based on the function of O-GlcNAcylation, we proposed that self-glycosylation was involved in the regulation of OGT.
A variety of biological and chemical approaches were applied in the study of self-glycosylation. Six potential glycosylation sites were found, and three of them had significant influence on the level of glycosylation. The glycosylation level of sOGT was higher in the cytoplasm than that in the nuclear, when it was overexpressed in the HEK293T cells. In the analysis of subcellular localization, the mount of T449A and T662A mutants was much less compared with the wild type, and the mount of other mutants was almost equal to the wild type. It was indicated that T449and T662might be involved in the translocation of sOGT. According to the results obtained with pull down and mass spectrometry, self-glycosylation was supposed to play an essential role in the interaction between sOGT and other proteins, which is associated with various cellular events. As a part of regulation of OGT, the function and mechanism of self-glycosylation'effect on OGT were not fully understood. We provided several clues for the further study of OGT self-glycosylation, as well as for the pathogenesis of chronic diseases associated with O-GlcNAcylation dysregulation.
O-GlcNAc糖基转移酶(OGT)负责催化O-GlcNAc糖基转移反应的发生。在人体内,OGT有三种亚型,即ncOGT、mOGT和sOGT,其结构的主要差异在于N末端TPR序列数目不同。由于三种亚型C末端催化结构域是完全相同的,因此其催化机制以及其与糖基供体的识别机制也应是相同的。因此在本课题中,我们选取了较为容易表达的sOGT作为研究对象,首先对其底物特异性进行了研究。以CKII十七肽为受体底物,我们探索sOGT对26种UDP-GlcNAc衍生物的催化活性。其中,UDP-6-deoxy-GlcNA、UDP-GlcNPr、UDP-6-deoxy-GalNAc和UDP-4-deoxy-GlcNAc四种化合物能够作为sOGT的供体底物。进一步对其中三种化合物的酶学常数的测定表明,UDP-GlcNAc糖基基团的C2位乙酰氨基上的取代、C6和C4位羟基的脱氧取代以及C4位羟基的异构都会削弱sOGT与供体底物的亲合力。通过OGT与底物的分子对接,并经定点突变验证,我们发现sOGT的Leu653的羰基氧和Thr560位的羟基能够与GlcNAc的C4/C6-OH形成氢键；Met501与UDP-GlcNAc的C2位乙酰氨基间的空间较小,不能容纳体积较大的取代基团,而其附近的疏水环境也利于疏水性取代基团的进入。上述结论为进一步了解OGT与糖基供体的相互作用以及其催化机制有一定帮助。
已有研究表明,OGT也可以作为自身催化O-GlcNAc糖基转移反应的底物,被糖基化修饰。基于O-GlcNAc修饰的功能,我们认为OGT的自身糖基化参与了对OGT功能的调控。
本课题运用多种生物学和化学研究方法对OGT的自身糖基化修饰现象进行了研究,发现了6个糖基化位点(S10, T12, S18, T38, S52, T449, T662),定点突变结果证实其中三个糖基化位点(S18,T38,T449)对sOGT糖基化水平有显著影响。通过对过表达的sOGT在细胞质和细胞核的分布及糖基化水平的研究发现,细胞质内sOGT的糖基化水平更高。通过激光共聚焦显微镜对不同sOGT突变体的亚细胞定位进行观察,与野生型相比较,发现T449A和T662A两个突变体转运入核明显减少,而其它突变体变化不大,这表明T449和T662两个位点可能与sOGT转运入核相关。通过Pull down技术以及生物质谱等研究方法,我们发现糖基化修饰对sOGT互作蛋白有显著影响,糖基化修饰sOGT能够作用的互作蛋白更多,差异蛋白中很多与重要的细胞生理活动相关。O-GlcNAc自身糖基化作为OGT自身调控机制的组成部分,其功能和作用机理尚不清晰,我们的研究对其中部分问题做出了解答,为进一步研究OGT自身调控机制奠定了基础,为OGT相关疾病发病机理的研究提供了参考。
O-GlcNAc modification, namely O-GlcNAcylation, is an essential post-translational modification with a single β-N-acetylglucosamine linked to Ser or Thr residues of various nucleocytoplasmic proteins. It contributes to various cellular cascades, including signal transduction, gene expression and protein trafficking. Dysregulation in O-GlcNAcylation is assumed to be tightly linked to chronic diseases, such as cancers, diabetes and neurodegenerative diseases.
O-Linked β-N-acetylglucosaminyl transferase (OGT) plays an important role in the glycosylation of proteins, which is involved in various cellular events. In human, three isoforms of OGT (short OGT [sOGT]; mitochondrial OGT [mOGT]; and nucleocytoplasmic OGT [ncOGT]) share the same catalytic domain, implying that they might adopt a similar catalytic mechanism, including sugar donor recognition. In this work, the sugar-nucleotide tolerance of sOGT was investigated. Among a series of uridine5'-diphosphate-N-acetylglucosamine (UDP-GlcNAc) analogs tested using the casein kinase Ⅱ(CKⅡ) peptide as the sugar acceptor, four compounds could be used by sOGT, including UDP-6-deoxy-GlcNAc, UDP-GlcNPr, UDP-6-deoxy-GalNAc and UDP-4-deoxy-GlcNAc. Determined values of Km showed that the substitution of the N-acyl group, deoxy modification of C6/C4-OH or epimerization of C4-OH of the GlcNAc in UDP-GlcNAc decreased its affinity to sOGT. A molecular docking study combined with site-directed mutagenesis indicated that the backbone carbonyl oxygen of Leu653and the hydroxyl group of Thr560in sOGT contributed to the recognition of the sugar moiety via hydrogen bonds. The close vicinity between Met501and the N-acyl group of GlcNPr, as well as the hydrophobic environment near Met501, were responsible for the selective binding of UDP-GlcNPr. These findings illustrate the interaction of OGT and sugar nucleotide donor, providing insights into the OGT catalytic mechanism.
Self-glycosylation of OGT was reported by several research groups. Based on the function of O-GlcNAcylation, we proposed that self-glycosylation was involved in the regulation of OGT.
A variety of biological and chemical approaches were applied in the study of self-glycosylation. Six potential glycosylation sites were found, and three of them had significant influence on the level of glycosylation. The glycosylation level of sOGT was higher in the cytoplasm than that in the nuclear, when it was overexpressed in the HEK293T cells. In the analysis of subcellular localization, the mount of T449A and T662A mutants was much less compared with the wild type, and the mount of other mutants was almost equal to the wild type. It was indicated that T449and T662might be involved in the translocation of sOGT. According to the results obtained with pull down and mass spectrometry, self-glycosylation was supposed to play an essential role in the interaction between sOGT and other proteins, which is associated with various cellular events. As a part of regulation of OGT, the function and mechanism of self-glycosylation'effect on OGT were not fully understood. We provided several clues for the further study of OGT self-glycosylation, as well as for the pathogenesis of chronic diseases associated with O-GlcNAcylation dysregulation.
引文
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