1r47
From Proteopedia
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'''Structure of human alpha-galactosidase''' | '''Structure of human alpha-galactosidase''' | ||
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[[Category: Garboczi, D N.]] | [[Category: Garboczi, D N.]] | ||
[[Category: Garman, S C.]] | [[Category: Garman, S C.]] | ||
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| - | + | [[Category: Glycoprotein]] | |
| - | [[Category: | + | [[Category: Glycosidase]] |
| - | [[Category: | + | [[Category: Lysosomal enzyme]] |
| - | [[Category: | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 07:03:10 2008'' |
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| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 04:03, 3 May 2008
Structure of human alpha-galactosidase
Contents |
Overview
Fabry disease is an X-linked lysosomal storage disease afflicting 1 in 40,000 males with chronic pain, vascular degeneration, cardiac impairment, and other symptoms. Deficiency in the lysosomal enzyme alpha-galactosidase (alpha-GAL) causes an accumulation of its substrate, which ultimately leads to Fabry disease symptoms. Here, we present the structure of the human alpha-GAL glycoprotein determined by X-ray crystallography. The structure is a homodimer with each monomer containing a (beta/alpha)8 domain with the active site and an antiparallel beta domain. N-linked carbohydrate appears at six sites in the glycoprotein dimer, revealing the basis for lysosomal transport via the mannose-6-phosphate receptor. To understand how the enzyme cleaves galactose from glycoproteins and glycolipids, we also determined the structure of the complex of alpha-GAL with its catalytic product. The catalytic mechanism of the enzyme is revealed by the location of two aspartic acid residues (D170 and D231), which act as a nucleophile and an acid/base, respectively. As a point mutation in alpha-GAL can lead to Fabry disease, we have catalogued and plotted the locations of 245 missense and nonsense mutations in the three-dimensional structure. The structure of human alpha-GAL brings Fabry disease into the realm of molecular diseases, where insights into the structural basis of the disease phenotypes might help guide the clinical treatment of patients.
Disease
Known disease associated with this structure: Fabry disease OMIM:[300644], Fabry disease, cardiac variant OMIM:[300644]
About this Structure
1R47 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
The molecular defect leading to Fabry disease: structure of human alpha-galactosidase., Garman SC, Garboczi DN, J Mol Biol. 2004 Mar 19;337(2):319-35. PMID:15003450 Page seeded by OCA on Sat May 3 07:03:10 2008
