1PU5

GM2-activator Protein crystal structure

Summary for 1PU5

• Entry DOI: 10.2210/pdb1pu5/pdb
• Related: 1G13
• Descriptor: Ganglioside GM2 activator, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID (3 entities in total)
• Functional Keywords: beta cup, large lipid binding pocket, protein dynamics, lipid binding protein
• Biological source: Homo sapiens (human)
• Cellular location: Lysosome: P17900
• Total number of polymer chains: 3
• Total formula weight: 53959.28

Authors

Wright, C.S.,Zhao, Q.,Rastinejad, F. (deposition date: 2003-06-24, release date: 2004-06-29, Last modification date: 2024-10-30)

Primary citation

Wright, C.S.,Zhao, Q.,Rastinejad, F.
Structural analysis of lipid complexes of GM2-activator protein.
J.Mol.Biol., 331:951-964, 2003

PubMed Abstract: 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.

PubMed: 12909021
DOI: 10.1016/S0022-2836(03)00794-0

Experimental method

X-RAY DIFFRACTION (1.9 Å)