Beta-Hexosaminidase

Structure of Human β-Hexosaminidase A and its association with Tay-Sachs disease

β-Hexosaminidase A is a lysosomal enzyme essential for the degradation of GM2 gangliosides. Deficiency of lysosomal β-Hexosaminidase A due to inherited defects in the α-subunit gene results in Tay-Sachs (TS) disease. The 3D structure of β-Hexosaminidase A was determined by the group of Michael N.G. James at the University of Alberta, Edmonton, Canada.^[1] The structure reveals an αβ-heterodimer, with each subunit having a functional active site. Only the α-subunit active site can hydrolyze GM2 gangliosides due to a flexible loop α₂₈₀GSEP₂₈₃ structure that is removed post-translationaly from β, and to the presence of α-Asn 423 and α-Arg 424. The loop structure is involved in binding the GM2 activator protein, while α-Arg424 is critical for binding the carboxylate group of the N-acetyl-neuraminic acid residue of GM2. Two active sites are present in the HexA dimer; one comprising residues from the α-subunit (R178 D207 H262 E323 D322 W373 W392 W460 Y421 R424 N423 E462) and a second one from residues of the β-subunit (R211 D240 H294 E355 D354 W405 W424 Y450 L453 D452 E491 W489). These active sites are located at the opening of TIM barrels at the interface between the α and β-subunits. The HexA undergoes glycosylation on the α and β-subunits; α-Asn 115, α-Asn 157 and α-Asn 295 β-Asn 84, β-Asn 142, β-Asn 190 and β-Asn 327. Mutations in the α-subunit are associated with TS disease and with Late Onset Tay Sachs disease (LOTS) (Chronic & Acute clinical phenotype). Interestingly, α-G269S is the most common mutation associated with LOTS disease. See also Beta-N-acetylhexosaminidase and Hexosaminidase (Hebrew).

3D Structures of Beta-Hexosaminidase

Beta-Hexosaminidase 3D structures