CDP-glycerol inhibits the synthesis of the functional O-mannosyl glycan of α-dystroglycan
CDP-glycerol inhibits the synthesis of the functional O-mannosyl glycan of α-dystroglycan
复制标题
CDP-甘油抑制 α-肌营养不良聚糖的功能性 O-甘露糖基聚糖的合成
DOI：
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发表时间：
2018
影响因子：
4.8
通讯作者：
T. Endo
中科院分区：
文献类型：
--
作者：
Rieko Imae;H. Manya;H. Tsumoto;K. Osumi;Tomohiro Tanaka;M. Mizuno;M. Kanagawa;Kazuhiro Kobayashi;T. Toda;T. Endo
α-Dystroglycan（α-DG）是一种高度糖基化的细胞表面层粘连蛋白受体。具有层粘连蛋白结合活性的α-DG的O-甘露糖聚糖的缺陷可引起α-肌营养不良聚糖病，一组先天性肌营养不良症。在功能性O-甘露糖基聚糖的生物合成途径中，其突变基因是α-肌营养不良聚糖病的基础的fuketin（FKTN）和fukutin-related protein（FKRP）依次将磷酸核糖醇（RboP）从CDP-Rbo转移，形成O-甘露糖基聚糖上的层粘连蛋白结合表位合成所需的串联RboP单元（RboP-RboP）。最近在重组α-DG中检测到RboP和磷酸甘油（GroP）取代的糖型。然而，目前尚不清楚GroP如何转移到O-甘露糖基聚糖或GroP取代是否影响O-甘露糖基聚糖的合成。在这里，我们报告说，除了具有RboP转移活性，FKTN和FKRP可以通过使用CDP-甘油（CDP-Gro）作为供体底物将GroP转移到O-甘露糖基聚糖。动力学实验表明，CDP-Gro是比CDP-Rbo效率更低的FKTN供体底物。我们还表明，由FKTN合成的GroP取代的糖型不作为FKRP的受体底物，因此，这种糖型不能进一步延长外聚糖链。最后，CDP-Gro抑制FKTN和FKRP的RboP转运活性。这些结果表明，CDP-Gro通过阻止聚糖链的进一步延长来抑制α-DG的功能性O-甘露糖基聚糖的合成。这是哺乳动物中GroP转移酶的首次报道。
α-Dystroglycan (α-DG) is a highly glycosylated cell-surface laminin receptor. Defects in the O-mannosyl glycan of an α-DG with laminin-binding activity can cause α-dystroglycanopathy, a group of congenital muscular dystrophies. In the biosynthetic pathway of functional O-mannosyl glycan, fukutin (FKTN) and fukutin-related protein (FKRP), whose mutated genes underlie α-dystroglycanopathy, sequentially transfer ribitol phosphate (RboP) from CDP-Rbo to form a tandem RboP unit (RboP–RboP) required for the synthesis of the laminin-binding epitope on O-mannosyl glycan. Both RboP- and glycerol phosphate (GroP)-substituted glycoforms have recently been detected in recombinant α-DG. However, it is unclear how GroP is transferred to the O-mannosyl glycan or whether GroP substitution affects the synthesis of the O-mannosyl glycan. Here, we report that, in addition to having RboP transfer activity, FKTN and FKRP can transfer GroP to O-mannosyl glycans by using CDP-glycerol (CDP-Gro) as a donor substrate. Kinetic experiments indicated that CDP-Gro is a less efficient donor substrate for FKTN than is CDP-Rbo. We also show that the GroP-substituted glycoform synthesized by FKTN does not serve as an acceptor substrate for FKRP and that therefore further elongation of the outer glycan chain cannot occur with this glycoform. Finally, CDP-Gro inhibited the RboP transfer activities of both FKTN and FKRP. These results suggest that CDP-Gro inhibits the synthesis of the functional O-mannosyl glycan of α-DG by preventing further elongation of the glycan chain. This is the first report of GroP transferases in mammals.
细胞表面层粘连蛋白锚定的丧失会促进肿瘤生长，并与不良的临床结果相关。
影响因子：
11.2
作者：
Akhavan A;Griffith OL;Soroceanu L;Leonoudakis D;Luciani-Torres MG;Daemen A;Gray JW;Muschler JL
通讯作者：
Muschler JL
DOI：
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发表时间：
2020
期刊：
--
影响因子：
--
作者：
Daniel Beltrán-Valero de Bernabé;Kei-ichiro Inamori;T. Yoshida-Moriguchi;C. Weydert;Hollie A. Harper;T. Willer;Michael D. Henry;Kevin P. Campbell
通讯作者：
Daniel Beltrán-Valero de Bernabé;Kei-ichiro Inamori;T. Yoshida-Moriguchi;C. Weydert;Hollie A. Harper;T. Willer;Michael D. Henry;Kevin P. Campbell
影响因子：
10.5
作者：
Brown S;Santa Maria JP Jr;Walker S
通讯作者：
Walker S