Crystal structure of human β-hexosaminidase B:: Understanding the molecular basis of Sandhoff and Tay-Sachs disease

JOURNAL OF MOLECULAR BIOLOGY

卷:327

Article

Mark, BL ; Mahuran, DJ ; Cherney, MM ; Zhao, DL ; Knapp, S ; James, MNG

关键词: hexosaminidase;    Sandhoff;    Tay-Sachs;    anchimeric assistance;    X-ray crystal structure;   

DOI  :  10.1016/S0022-2836(03)00216-X

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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