Crystal structure of human β-hexosaminidase B:: Understanding the molecular basis of Sandhoff and Tay-Sachs disease
Crystal structure of human β-hexosaminidase B:: Understanding the molecular basis of Sandhoff and Tay-Sachs disease
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DOI：
10.1016/s0022-2836(03)00216-x
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发表时间：
2003-04-11
影响因子：
5.6
通讯作者：
James, MNG
中科院分区：
文献类型：
--
作者：
Mark, BL;Mahuran, DJ;James, MNG
在人类中，存在两种主要的β-氨基己糖苷酶同工酶：Hex A和Hex B。Hex A是亚基α和β的异二聚体（60%同一性），而Hex B是β亚基的同二聚体。对人β-氨基己糖苷酶的兴趣源于其与泰-萨二氏病和桑德霍夫病的相关性;这些是由G（M2）-神经节苷脂（G（M2））异常蓄积引起的典型溶酶体贮积症。Hex A通过去除末端N-乙酰基-D-半乳糖胺（β-GalNAc）残基降解G（M2），这种活性需要G（M2）-激活剂，一种溶解神经节苷脂I以呈递给Hex A的蛋白质。我们在这里提出的晶体结构的人六角B，单独（2.4埃）和复杂的机械抑制剂GalNAc-异法戈明（2.2埃）或NAG-噻唑啉（2.5埃）。从这些，和已知的X-射线结构的G（M2）-激活剂，我们模拟了六角A与激活剂和神经节苷脂复合。总之，我们的晶体学和建模数据证明了α和β亚基如何二聚形成Hex A或Hex B，这些同工酶如何水解不同的底物，以及有多少记录的点突变导致Sandhoff病（β亚基突变）和Tay-Sachs病（α亚基突变）。(C)2003爱思唯尔科技有限公司版权所有。
In humans, two major beta-hexosaminidase isoenzymes exist: Hex A and Hex B. Hex A is a heterodimer of subunits alpha and beta (60% identity), whereas Hex B is a homodimer of beta-subunits. Interest in human beta-hexosaminidase stems from its association with Tay-Sachs and Sandhoff disease; these are prototypical lysosomal storage disorders resulting from the abnormal accumulation of G(M2)-ganglioside (G(M2)). Hex A degrades G(M2) by removing a terminal N-acetyl-D-galactosamine (beta-GalNAc) residue, and this activity requires the G(M2)-activator, a protein which solubilizes the ganglioside I for presentation to Hex A. We present here the crystal structure of human Hex B, alone (2.4 Angstrom) and in complex with the mechanistic inhibitors GalNAc-isofagomine (2.2 Angstrom) or NAG-thiazoline (2.5 Angstrom). From these, and the known X-ray structure of the G(M2)-activator, we have modeled Hex A in complex with the activator and ganglioside. Together, our crystallographic and modeling data demonstrate how a and beta-subunits dimerize to form either Hex A or Hex B, how these isoenzymes hydrolyze diverse substrates, and how many documented point mutations cause Sandhoff disease (beta-subunit mutations) and Tay-Sachs disease (alpha-subunit mutations). (C) 2003 Elsevier Science Ltd. All rights reserved.