Title : The structure of human
GALNS reveals the molecular basis for mucopolysaccharidosis IV A.
Lysosomal enzymes catalyze the breakdown of macromolecules in the cell
Abstract :
- In humans, loss of activity of a lysosomal enzyme leads to an inherited metabolic defect known as a lysosomal storage disorder
- The human lysosomal enzyme galactosamine-6- sulfatase ( GALNS , also known as N-acetylgalactosamine-6-sulfatase and GalN6S; E.C. 3.1.6.4) is deficient in patients with the lysosomal storage disease mucopolysaccharidosis IV A (also known as MPS IV A and Morquio A)
- Here, we report the three-dimensional structure of human GALNS , determined by X-ray crystallography at 2.2Å resolution
- The structure reveals a catalytic gem diol nucleophile derived from modification of a cysteine side chain
- The active site of GALNS is a large, positively charged trench suitable for binding polyanionic substrates such as keratan sulfate and chondroitin-6-sulfate
- Enzymatic assays on the insect-cell-expressed human GALNS indicate activity against synthetic substrates and inhibition by both substrate and product
- Mapping 120 MPS IV A missense mutations onto the structure reveals that a majority of mutations affect the hydrophobic core of the structure, indicating that most MPS IV A cases result from misfolding of GALNS
- Comparison of the structure of GALNS to paralogous sulfatases shows a wide variety of active-site geometries in the family but strict conservation of the catalytic machinery
- Overall, the structure and the known mutations establish the molecular basis for MPS IV A and for the larger MPS family of diseases
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