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

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).

• Authors: Brian L Mark, Don J Mahuran, Maia M Cherney, Dalian Zhao, Spencer Knapp, Michael N G James
• Journal: Journal of molecular biology (J Mol Biol) Vol. 327 Issue 5 Pg. 1093-109 (Apr 11 2003) ISSN: 0022-2836 [Print] Netherlands
• PMID: 12662933 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hexosaminidase A
• Hexosaminidase B
• beta-N-Acetylhexosaminidases

Topics

• Amino Acid Sequence
• Binding Sites
• Crystallography, X-Ray
• Dimerization
• Hexosaminidase A
• Hexosaminidase B
• Humans
• Models, Molecular
• Molecular Sequence Data
• Protein Conformation
• Sandhoff Disease (enzymology)
• Sequence Homology, Amino Acid
• Tay-Sachs Disease (enzymology)
• beta-N-Acetylhexosaminidases (chemistry)