Beta-Hexosaminidase

From Proteopedia

Revision as of 09:27, 19 December 2010

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 in Canada and published in J. Mol. Biol. (2006) 359, 913-929. 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-translational from β, and to the presence of αAsn423 and αArg424. The loop structure is involved in binding the GM2 activator protein, while αArg424 is critical for binding the carboxylate group of the N-acetyl-neuraminic acid residue of GM2. Two active sites are present in HexA dimmer; 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 a TIM barrels at the interface between the α and β-subunits. The HexA undergoes glycosylation at the α and β-subunits; αAsn115, αAsn157 and αAsn295 βAsn84, βAsn142, βAsn190 and βAsn327. Mutations (see Table) in the a-subunit are associate with TS disease and with Late Onset Tay Sachs disease (LOTS). Interestingly, αGly269S is the most common mutation associated with LOTS disease.