Tissue-Specific Regulation of HNK-1 Biosynthesis by Bisecting GlcNAc.
Tissue-Specific Regulation of HNK-1 Biosynthesis by Bisecting GlcNAc.
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DOI：
10.3390/molecules26175176
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发表时间：
2021-08-26
期刊：
影响因子：
--
通讯作者：
Kizuka Y
中科院分区：
文献类型：
--
作者：
Kawade H;Morise J;Mishra SK;Tsujioka S;Oka S;Kizuka Y
人自然杀伤细胞-1（HNK-1）是一种硫酸化糖基表位，调节细胞粘附和突触功能。HNK-1及其非硫酸化形式分别在脑和肾中特异性表达，由两种同源糖基转移酶（脑中的GlcAT-P和肾中的GlcAT-S）明显生物合成。然而，很大程度上还不清楚这些同工酶的活性是如何在体内调节的。我们最近发现，二等分GlcNAc，N-聚糖中的分支糖，抑制大脑中GlcAT-P活性和HNK-1表达。在此，我们观察到，在缺乏二等分GlcNAc的突变小鼠中，肾脏中非硫酸化HNK-1的表达出乎意料地不变。这表明HNK-1在脑和肾中的生物合成受平分GlcNAc的差异调节。从机制上讲，体外活性测定表明，等分GlcNAc抑制GlcAT-P的活性，但不抑制GlcAT-S的活性。此外，分子动力学模拟显示GlcAT-P与二等分N-聚糖底物的结合较差，而GlcAT-S与二等分和非二等分N-聚糖的结合相似。这些发现揭示了HNK-1合成的高度同源同工酶的差异，突出了通过平分GlcNAc对HNK-1合成的组织特异性调节的新机制。
Human natural killer—1 (HNK-1) is a sulfated glyco-epitope regulating cell adhesion and synaptic functions. HNK-1 and its non-sulfated forms, which are specifically expressed in the brain and the kidney, respectively, are distinctly biosynthesized by two homologous glycosyltransferases: GlcAT-P in the brain and GlcAT-S in the kidney. However, it is largely unclear how the activity of these isozymes is regulated in vivo. We recently found that bisecting GlcNAc, a branching sugar in N-glycan, suppresses both GlcAT-P activity and HNK-1 expression in the brain. Here, we observed that the expression of non-sulfated HNK-1 in the kidney is unexpectedly unaltered in mutant mice lacking bisecting GlcNAc. This suggests that the biosynthesis of HNK-1 in the brain and the kidney are differentially regulated by bisecting GlcNAc. Mechanistically, in vitro activity assays demonstrated that bisecting GlcNAc inhibits the activity of GlcAT-P but not that of GlcAT-S. Furthermore, molecular dynamics simulation showed that GlcAT-P binds poorly to bisected N-glycan substrates, whereas GlcAT-S binds similarly to bisected and non-bisected N-glycans. These findings revealed the difference of the highly homologous isozymes for HNK-1 synthesis, highlighting the novel mechanism of the tissue-specific regulation of HNK-1 synthesis by bisecting GlcNAc.
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DOI：
10.1021/jp505875v
发表时间：
2015-01-22
期刊：
The journal of physical chemistry. B
影响因子：
--
作者：
Li P;Song LF;Merz KM Jr
通讯作者：
Merz KM Jr
影响因子：
11.1
作者：
Kizuka Y;Kitazume S;Fujinawa R;Saito T;Iwata N;Saido TC;Nakano M;Yamaguchi Y;Hashimoto Y;Staufenbiel M;Hatsuta H;Murayama S;Manya H;Endo T;Taniguchi N
通讯作者：
Taniguchi N
影响因子：
5.1
作者：
Garcia-Ayllon, Maria-Salud;Botella-Lopez, Arancha;Saez-Valero, Javier
通讯作者：
Saez-Valero, Javier
影响因子：
2.7
作者：
GU, JG;NISHIKAWA, A;TANIGUCHI, N
通讯作者：
TANIGUCHI, N
影响因子：
3.3
作者：
Morita, I.;Kakuda, S.;Oka, S.
通讯作者：
Oka, S.