Crystal structure of human GM2-activator protein with a novel beta-cup topology

J Mol Biol. 2000 Dec 1;304(3):411-22. doi: 10.1006/jmbi.2000.4225.


GM2 activator protein (GM2-AP) belongs to a small group of non- enzymatic lysosomal proteins that act as cofactors in the sequential degradation of gangliosides. It has been postulated that GM2-AP extracts single GM2 molecules from membranes and presents them in soluble form to beta-hexosaminidase A for cleavage of N-acetyl-d-galactosamine and conversion to GM3. The high affinity of GM2-AP for GM2 is based on specfic recognition of the oligosaccharide moiety as well as the ceramide lipid tail. Genetic defects in GM2-AP result in an atypical form of Tay-Sachs disease known as variant AB GM2 gangliosidosis. The 2.0 A resolution crystal structure of GM2-AP reported here reveals a previously unobserved fold whose main feature is an eight-stranded cup-shaped anti-parallel beta-pleated sheet. The striking feature of the GM2-AP structure is that it possesses an accessible central hydrophobic cavity rather than a buried hydrophobic core. The dimensions of this cavity (12 Ax14 Ax22 A) are suitable for binding 18-carbon lipid acyl chains. Flexible surface loops and a short alpha-helix decorate the mouth of the beta-cup and may control lipid entry to the cavity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Ceramides / metabolism
  • Crystallography, X-Ray
  • G(M2) Activator Protein
  • Gangliosidoses, GM2 / genetics
  • Humans
  • Hydrogen Bonding
  • Lipid Metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation / genetics
  • Pliability
  • Protein Structure, Secondary
  • Proteins / chemistry*
  • Proteins / genetics
  • Proteins / metabolism*
  • Static Electricity


  • Ceramides
  • G(M2) Activator Protein
  • Proteins

Associated data

  • PDB/1G13