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Crystal structure of human beta-hexosaminidase B: understanding the molecular basis of Sandhoff and Tay-Sachs disease.

Authors
  • Mark, Brian L1
  • Mahuran, Don J
  • Cherney, Maia M
  • Zhao, Dalian
  • Knapp, Spencer
  • James, Michael N G
  • 1 Canadian Institutes of Heath Research Group in Protein Structure and Function, Department of Biochemistry, University of Alberta, T6G 2H7, Edmonton, Alt., Canada. , (Canada)
Type
Published Article
Journal
Journal of molecular biology
Publication Date
Apr 11, 2003
Volume
327
Issue
5
Pages
1093–1109
Identifiers
PMID: 12662933
Source
Medline
License
Unknown

Abstract

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 for presentation to Hex A. We present here the crystal structure of human Hex B, alone (2.4A) and in complex with the mechanistic inhibitors GalNAc-isofagomine (2.2A) or NAG-thiazoline (2.5A). 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 alpha 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).

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