Crystal Structure of Human β-Hexosaminidase B: Understanding the Molecular Basis of Sandhoff and Tay-Sachs Disease

Brian L. Mark, Don J. Mahuran, Maia M. Cherney, Dalian Zhao, Spencer Knapp, Michael N.G. James

Research output: Contribution to journalArticlepeer-review

173 Scopus citations

Abstract

In humans, two major β-hexosaminidase isoenzymes exist: Hex A and Hex B. Hex A is a heterodimer of subunits α and β (60% identity), whereas Hex B is a homodimer of β-subunits. Interest in human β-hexosaminidase stems from its association with Tay-Sachs and Sandhoff disease; these are prototypical lysosomal storage disorders resulting from the abnormal accumulation of GM2-ganglioside (GM2). Hex A degrades GM2 by removing a terminal N-acetyl-D-galactosamine (β-GalNAc) residue, and this activity requires the GM2-activator, a protein which solubilizes the ganglioside for presentation to Hex A. We present here the crystal structure of human Hex B, alone (2.4Å) and in complex with the mechanistic inhibitors GalNAc-isofagomine (2.2Å) or NAG-thiazoline (2.5Å). From these, and the known X-ray structure of the GM2-activator, we have modeled Hex A in complex with the activator and ganglioside. Together, our crystallographic and modeling data demonstrate how α and β-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 (β-subunit mutations) and Tay-Sachs disease (α-subunit mutations).

Original languageEnglish (US)
Pages (from-to)1093-1109
Number of pages17
JournalJournal of molecular biology
Volume327
Issue number5
DOIs
StatePublished - Apr 11 2003

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

Keywords

  • Anchimeric assistance
  • Hexosaminidase
  • Sandhoff
  • Tay-Sachs
  • X-ray crystal structure

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