4FDI

The molecular basis of mucopolysaccharidosis IV A

Summary for 4FDI

• Entry DOI: 10.2210/pdb4fdi/pdb
• Related: 4FDJ
• Descriptor: N-acetylgalactosamine-6-sulfatase, 2-acetamido-2-deoxy-beta-D-glucopyranose, CALCIUM ION, ... (6 entities in total)
• Functional Keywords: glycoprotein, enzyme replacement therapy, sulfatase, formylglycine, n-linked glycosylation, lysosomal enzyme, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Lysosome: P34059
• Total number of polymer chains: 2
• Total formula weight: 114136.28

Authors

Rivera-Colon, Y.,Garman, S.C. (deposition date: 2012-05-28, release date: 2012-09-05, Last modification date: 2024-11-06)

Primary citation

Rivera-Colon, Y.,Schutsky, E.K.,Kita, A.Z.,Garman, S.C.
The Structure of Human GALNS Reveals the Molecular Basis for Mucopolysaccharidosis IV A.
J.Mol.Biol., 423:736-751, 2012

PubMed Abstract: Lysosomal enzymes catalyze the breakdown of macromolecules in the cell. 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.

PubMed: 22940367
DOI: 10.1016/j.jmb.2012.08.020

Experimental method

X-RAY DIFFRACTION (2.2 Å)