Crystal structure of human GM2-activator protein with a novel beta-cup topology.
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.
Wright
C S
CS
Department of Pharmacology, X-ray Crystallography Laboratory, University of Virginia, Charlottesville, VA 22908-0735, USA. csw2n@virginia.edu
Li
S C
SC
Rastinejad
F
F
D000595:Amino Acid Sequence; D001665:Binding Sites; D002518:Ceramides / Q000378:metabolism; D018360:Crystallography, X-Ray; D049289:G(M2) Activator Protein; D020143:Gangliosidoses, GM2 / Q000235:genetics; D006801:Humans; D006860:Hydrogen Bonding; D050356:Lipid Metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D018583:Pliability; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D055672:Static Electricity
D002518:Ceramides; D049289:G(M2) Activator Protein; D011506:Proteins