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

GM2 activator protein (GM2-AP) belongs to a small group of nonenzymatic lys osomal proteins that act as cofactors in the sequential degradation of gang liosides. 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 af finity of GM2-AP for GM2 is based on specfic recognition of the oligosaccha ride moiety as well as the ceramide lipid tail. Genetic defects in GM2-AP r esult in an atypical form of Tay-Sachs disease known as variant AB GM2 gang liosidosis. The 2.0 Angstrom resolution crystal structure of GM2-AP reporte d 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 hydroph obic cavity rather than a buried hydrophobic core. The dimensions of this c avity (12 Angstrom X 14 Angstrom X 22 Angstrom) are suitable for binding 13 -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 cavi ty. (C) 2000 Academic Press.