Download MendeleyCrystal structure of Human beta-hexosaminidase B: Understanding the molecular basis of Sandhoff and Tay-Sachs disease
Mark, B.L., Mahuran, D.J., Cherney, M.M., Zhao, D., Knapp, S., James, M.N.G.(2003) J Mol Biol 327: 1093-1109
- PubMed: 12662933
- DOI: https://doi.org/10.1016/s0022-2836(03)00216-x
- Primary Citation of Related Structures:
1NOU, 1NOW, 1NP0 - PubMed 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).
Organizational Affiliation:
Canadian Institutes of Heath Research Group in Protein Structure and Function, Department of Biochemistry, University of Alberta, T6G 2H7, Edmonton, Alt., Canada.
