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PDBsum entry 1pub
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Lipid binding protein
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PDB id
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1pub
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structural analysis of lipid complexes of gm2-Activator protein.
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Authors
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C.S.Wright,
Q.Zhao,
F.Rastinejad.
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Ref.
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J Mol Biol, 2003,
331,
951-964.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Figure 2.
Figure 2. A stereoscopic view of the two positions of the
mobile W131 loop observed in GM2-AP3. The stick models are
color-coded blue for monomer A with the loop in the exposed
position, and magenta for monomer C with the loop folded in
making contact with hydrophobic residues (shown in yellow). The
broken line indicates the invariant hydrogen bond between the
carbonyl oxygen atom of T133 and the OH group of Y137, and the
arrow points at the C^a-CO bond of T133, serving as a flexible
hinge with the C-terminal T134 fixed. The Figure was generated
with DINO.
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Figure 6.
Figure 6. A representation of the proposed interaction of
GM2-AP with a lipid monolayer. The open structure of GM2-AP1 is
depicted as ribbon model (generated in DINO) with its apolar and
mobile loops colored purple. Basic amino acid side-chains in
this region are shown in blue (K57, K65, R138, K154), and the
two tryptophan residues (W63, W131) are shown in yellow. In
structure A, the apolar loop is shown to interface with a PC
monolayer. Structure B represents the observed crystal complex
of GM2-AP1.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2003,
331,
951-964)
copyright 2003.
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