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The molecular defect leading to Fabry disease: structure of human alpha-galactosidase

Scott C Garman1, David N Garboczi

  • 1Structural Biology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Twinbrook II, 12441 Parklawn Drive, Rockville, MD 20852, USA. sgarman@niaid.nih.gov

Journal of Molecular Biology
|March 9, 2004
PubMed

Insights

Researchers determined the 3D structure of human alpha-galactosidase (alpha-GAL), revealing its catalytic mechanism and mutation sites. This structural insight into alpha-GAL advances understanding of Fabry disease.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Genetics

Background:

  • Fabry disease is an X-linked lysosomal storage disorder caused by alpha-galactosidase (alpha-GAL) deficiency.
  • This deficiency leads to substrate accumulation, causing symptoms like chronic pain and organ damage.

Purpose of the Study:

  • To elucidate the three-dimensional structure of human alpha-GAL.
  • To understand the enzyme's catalytic mechanism and substrate binding.
  • To map Fabry disease-associated mutations onto the protein structure.

Main Methods:

  • X-ray crystallography was used to determine the structure of the human alpha-GAL glycoprotein.
  • The structure of the alpha-GAL-product complex was determined to reveal the catalytic mechanism.
  • Missense and nonsense mutations were cataloged and mapped onto the 3D structure.

Main Results:

  • The human alpha-GAL structure was determined as a homodimer with distinct functional domains.
  • N-linked glycosylation sites were identified, explaining lysosomal transport via the mannose-6-phosphate receptor.
  • The catalytic mechanism was elucidated, highlighting the roles of aspartic acid residues D170 and D231.
  • 245 disease-associated mutations were mapped onto the structure.

Conclusions:

  • The determined structure provides a molecular basis for understanding Fabry disease.
  • Structural insights can guide the development of targeted therapies for Fabry disease.
  • This work positions Fabry disease as a molecular disease with a defined structural basis.

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