1pu5
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GM2-activator Protein crystal structure
OverviewOverview
The GM2-activator protein (GM2-AP) is a small lysosomal lipid transfer, protein essential for the hydrolytic conversion of ganglioside GM2 to GM3, by beta-hexosaminidase A. The crystal structure of human apo-GM2-AP is, known to consist of a novel beta-cup fold with a spacious hydrophobic, interior. Here, we present two new structures of GM2-AP with bound lipids, showing two different lipid-binding modes within the apolar pocket. The, 1.9A structure with GM2 bound shows the position of the ceramide tail and, significant conformational differences among the three molecular copies in, the asymmetric unit. The tetrasaccharide head group is not visible and is, presumed to be disordered. However, its general position could be, established through modeling. The structure of a low-pH crystal, determined at 2.5A resolution, has a significantly enlarged hydrophobic, channel that merges with the apolar pocket. Electron density inside the, pocket and channel suggests the presence of a trapped phospholipid, molecule. Structure alignments among the four crystallographically unique, monomers provide information on the potential role for lipid binding of, flexible chain segments at the rim of the cavity opening. Two discrete, orientations of the S130-T133 loop define an open and a closed, configuration of the hydrophobic channel that merges with the apolar, pocket. We propose: (i) that the low-pH structure represents an active, membrane-binding conformation; (ii) that the mobile S130-T133 loop serves, as a gate for passage of ligand into the apolar pocket; and (iii) that, this loop and the adjacent apolar V59-W63 loop form a surface patch with, two exposed tryptophan residues that could interface with lipid bilayers.
DiseaseDisease
Known disease associated with this structure: GM2-gangliosidosis, AB variant OMIM:[272750]
About this StructureAbout this Structure
1PU5 is a Single protein structure of sequence from Homo sapiens with EPE as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Structural analysis of lipid complexes of GM2-activator protein., Wright CS, Zhao Q, Rastinejad F, J Mol Biol. 2003 Aug 22;331(4):951-64. PMID:12909021
Page seeded by OCA on Mon Nov 12 18:47:21 2007