Beta-Hexosaminidase

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===Structure of Human β-Hexosaminidase A and its association with Tay-Sachs disease===
===Structure of Human β-Hexosaminidase A and its association with Tay-Sachs disease===
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&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;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.<ref>PMID:16698036</ref> The structure reveals an <scene name='Beta-Hexosaminidase/Subunits/4'>αβ-heterodimer</scene>, with each subunit having a functional active site. Only the <scene name='Beta-Hexosaminidase/Alpha/2'>α-subunit</scene> active site can hydrolyze GM2 gangliosides due to <scene name='Beta-Hexosaminidase/Gsep/6'>a flexible loop</scene> α<sub>280</sub>GSEP<sub>283</sub> structure that is removed post-translational from β, and to the presence of <scene name='Beta-Hexosaminidase/4234/3'>α-Asn 423 and α-Arg 424</scene>. The <scene name='Beta-Hexosaminidase/Gsep_out/1'>loop structure</scene> 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.
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&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;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.<ref>PMID:16698036</ref> The structure reveals an <scene name='Beta-Hexosaminidase/Subunits/4'>αβ-heterodimer</scene>, with each subunit having a functional active site. Only the <scene name='Beta-Hexosaminidase/Alpha/2'>α-subunit</scene> active site can hydrolyze GM2 gangliosides due to <scene name='Beta-Hexosaminidase/Gsep/6'>a flexible loop</scene> α<sub>280</sub>GSEP<sub>283</sub> structure that is removed post-translational from β, and to the presence of <scene name='Beta-Hexosaminidase/4234/3'>α-Asn 423 and α-Arg 424</scene>. The <scene name='Beta-Hexosaminidase/Gsep_out/2'>loop structure</scene> 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.
===References===
===References===
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Revision as of 10:55, 19 December 2010

Crystal Structure of Human β-Hexosaminidase, (2gjx)

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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.[1] The structure reveals an , with each subunit having a functional active site. Only the active site can hydrolyze GM2 gangliosides due to α280GSEP283 structure that is removed post-translational from β, and to the presence of . The 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.

References

  1. ↑ Lemieux MJ, Mark BL, Cherney MM, Withers SG, Mahuran DJ, James MN. Crystallographic structure of human beta-hexosaminidase A: interpretation of Tay-Sachs mutations and loss of GM2 ganglioside hydrolysis. J Mol Biol. 2006 Jun 16;359(4):913-29. Epub 2006 Apr 27. PMID:16698036 doi:http://dx.doi.org/10.1016/j.jmb.2006.04.004
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