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

BL Mark, DJ Mahuran, MM Cherney, D Zhao… - Journal of molecular …, 2003 - Elsevier
BL Mark, DJ Mahuran, MM Cherney, D Zhao, S Knapp, MNG James
Journal of molecular biology, 2003Elsevier
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 …
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).
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